Compositions and methods for the treatment of presbyopia

ABSTRACT

The invention provides compositions and methods for the treatment of presbyopia. The compositions preferably comprise aceclidine and a polyol. The compositions optionally contain a cycloplegic agent, a surfactant, a viscosity enhancer, an osmolarity modifier and a preservative.

BACKGROUND OF THE INVENTION

As a person ages the minimum distance from the eye at which an objectwill come into focus, provided distance vision is corrected or isexcellent unaided, increases. For example, a 10 year-old can focus on anobject or a “focal point” only three inches (0.072 meters) from theireye while still retaining excellent distance vision; a 40 year-old atsix inches (0.15 meters); and a 60 year-old at an inconvenient 39 inches(1.0 meter). This condition of increasing minimum focal length inindividuals with excellent unaided distance vision is called presbyopia,loosely translated as “old-man eye”.

Excellent unaided distance vision is also known as emmetropia. Theinability to focus on distant focal points is known as myopia and theinability to focus on near focal points is known as hyperopia.Specifically, “distance” vision is considered any focal point 1 meter ormore from the eye and near vision is any focal point less than 1 meterfrom the eye. The minimum focal length at which an object will come intofocus is known as the “near point”. The change in focus from distance tothe near point and any focal point in between is called accommodation.Accommodation is often measured in diopters. Diopters are calculated bytaking the reciprocal of the focal length (in meters). For example, thedecrease in accommodation from a 10 year-old eye to a 60 year-old eye isabout 13 diopters (1±0.072 meters=13.89 diopters; 1±1 meter=1 diopter).

The highest incidence of first complaint of presbyopia occurs in peopleages 42-44. Presbyopia occurs because as a person ages the eye'saccommodative ability which uses near reflex-pupil constriction,convergence of the eyes and particularly ciliary muscle contraction,decreases. This reduction in accommodation results in an inadequatechange in the normal thickening and increased curvature of the anteriorsurface of the lens that is necessary for the shift in focus fromdistant objects to near objects. Important near focus tasks affected bypresbyopia include viewing computer screens (21 inches) and readingprint (16 inches).

Presbyopia is a normal and inevitable effect of ageing and is the firstunmistakable sign for many in their forties that they are getting older.One study found that more than 1 billion people worldwide werepresbyopic in 2005. This same study predicted that number to almostdouble by the year 2050. If everyone over the age of 45 is considered tobe presbyopic, then an estimated 122 million people in the United Statesalone had presbyopia in 2010. As baby boomers reach the critical age,this number is only going to increase.

Presbyopia carries with it a stigma resulting from the limitation inability to quickly function at many tasks requiring focusing at bothdistant and near points, which once occurred almost immediately. In thepresbyopic patient, these tasks can be performed only by the use ofeyeglasses, contact lenses or after undergoing invasive surgery. Onesuch optical modification, the monovision procedure, can be executedwith the use of glasses, contact lenses or even surgery. The monovisionprocedure corrects one eye for near focus and the other eye for distancefocus. However, monovision correction is normally accompanied by loss ofdepth perception and distance vision particularly in dim light (e.g.night). Other surgical procedures that have been developed to relievepresbyopia include: (1) the implantation of intraocular lenses(INTRACOR®; registered trademark of Technolas Perfect Vision GMBH); (2)reshaping of the cornea (PresbyLASIK and conductive keratoplasty); (3)scleral band expansion; and (4) implantation of corneal inlays (FlexivueMicrolens®; registered trademark of PresbiBio LLC, Kamra®; registeredtrademark of AcuFocus, Inc. and Vue+). Kamra® corneal inlaysmanufactured by AcuFocus work by inlaying a pinhole on the cornea toincrease the depth of focus. A similar effect can be achieved withgeneral miotic agents, such as pilocarpine (a non-selective muscarinicacetylcholine receptor agonist), carbachol (a non-selective muscarinicacetylcholine receptor agonist), and phospholine iodide (anacetylcholinesterase inhibitor). These general miotic agents triggerincreased ciliary muscle contraction and induce accommodation of anyremaining reserves, improving near vision at the expense of distancevision in individuals who still retain some accommodative function.While these general miotic agents also create improved depth of focusvia a pinhole effect induced by pupillary miosis (i.e. constriction), tothe degree accommodation occurs, the pinhole effect only partiallyoffsets the induced accommodative myopia for distance. In some cases,such as with pilocarpine or carbachol, the induced accommodation maycreate up to 5 diopters or more of induced myopia resulting in inducedmyopia causing blurred distance vision generally and during shift of thefocal point from distance to near. These general miotic agents alsocause substantial redness, severe nasal congestion and create ciliarymuscle spasms, which commonly induces discomfort that can be severe andlong-lasting. In extreme cases, such ciliary muscle spasms can result inretinal detachment.

Miotic agents have been described in various patent and patentapplications for the treatment of presbyopia. U.S. Pat. Nos. 6,291,466and 6,410,544 describe the use of pilocarpine to regulate thecontraction of ciliary muscles to restore the eye to its resting stateand potentially restore its accommodative abilities.

U.S. Pat. No. 8,524,758 describes the use of pilocarpine with thenon-steroidal anti-inflammatory, diclofenac, to reduce brow ache fromciliary spasm and increase the time in which the ciliary musclecontraction is regulated. International PCT Application PublicationWO/2013/041967 describes the use of pilocarpine with oxymetazoline ormeloxicam to temporarily overcome ocular conditions such as presbyopia.

U.S. Pat. No. 8,299,079 (HEK Development LLC) describes the use ofdirect acting general miotic agents such as pilocarpine, carbachol andphospholine iodide with the alpha 2 selective vasoconstrictorbrimonidine at a concentration from 0.05% to 3.0% w/v. However, the useof brimonidine concentrations of about 0.20% (or any at or above 0.05%)w/v induces ciliary spasm with often migraine intensity brow and/or headaches, and frequently results in increased rebound hyperemia. Forexample, rebound redness occurs in 25% of patients using brimonidine0.20% w/v (Alphagan®, registered trademark of Allergan, Inc.) twicedaily.

US Patent Application Publication No. 2014/0113946 describes the use ofpilocarpine with the alpha 1 and mild alpha 2 agonist vasoconstrictoroxymetazoline, demonstrating limitations in distance sharpness andduration, whereby a cohort largely restricted to mild hyperopes isrequired to neutralize the induced myopia (Table 1). Of the 16 eyestreated only three were −0.25 to −0.50 diopters, and eight were mildlyhyperopic. Of the −0.50 diopter eyes two were reduced to 20.40 distance.Further, duration was limited as full effect became diminished in aboutfour hours. Pupil size range was from 2.0 mm to 2.7 mm, where enhancednear effect and distance sharpness from depth of focus was minimal toabsent.

These attempts at miotic treatment for presbyopia all induce transientmyopia of several diopters reducing distance vision to about legalblindness or worse at the expense of improved near vision for the fullduration of their action, typically lasting several hours. This myopiceffect is amplified by the exponential drop off in distance acuity witheven small increments of nominal myopia in terms of unaided untreatedvision. For example, a person having mild myopia (e.g. sphericalequivalents of −0.25 D, −0.50 D) that is usually associated with glassesfree distance vision, typically will have several lines of distancevision loss after instillation of pilocarpine 1% (i.e. sphericalequivalent of −0.75 D.).

Miotics historically used to treat glaucoma, other than pilocarpine,particularly aceclidine, are also associated with ciliary spasm, browand/or headache, and myopic blur. Further, aceclidine is unstable insolution. Normally, aceclidine is stored in a two-bottle system; onebottle containing the lyophilized aceclidine and the second bottlecontaining the diluent necessary to reconstitute the lyophilizedaceclidine before topical instillation. However, the primary issue withits use as a presbyopic miotic is the attendant pain and in some casesdistance blur that may be induced.

U.S. Pat. No. 9,089,562 describes a composition containing aceclidinecombined with a cycloplegic agent, such that in preferred embodimentsaceclidine 1.45% is combined with tropicamide 0.042%. The addition ofthe cycloplegic agent allows for useful distance and improved nearvision without ciliary spasm, which is induced by the use of aceclidinealone. Further, aceclidine and the cycloplegic agent require particularnarrowly defined ratios and ranges of concentrations relative to eachother such that complications in the manufacturing and regulatoryprocess, particularly the need for lyophilization of aceclidine andattendant effects of cryoprecipitant required, result in reducedefficacy of the defined ranges and ratios of concentrations of U.S. Pat.No. 9,089,562. Due to these medical and practical inefficiencies, anaceclidine composition requiring same or slightly higher concentrationsof aceclidine and much lower concentrations than U.S. Pat. No. 9,089,562or in some cases no cycloplegic agent, while allowing for formulationmodifications to lyophilize aceclidine would be preferred for thetreatment of presbyopia with necessary commercially stable formulations.However, to date, no aceclidine composition with amounts of cycloplegicagent lower than that claimed in U.S. Pat. No. 9,089,562 has beeneffective to treat presbyopia because, as mentioned above, aceclidinealone, particularly young and middle-aged presbyopes (ages 45 to 58),severe ciliary spasms and may cause accommodative induced distance blurin some subjects.

Thus, there is a need in the art for a treatment of presbyopia that isnon-invasive and convenient with minimal side effects. Specifically,there is a need for an ophthalmological composition that will allow aperson suffering from presbyopia to focus on near objects withoutsignificant side effects such as diminished distance vision, blurredvision, pain, redness, impaired night driving or incapacitating dimlight vision, induced nasal congestion, or risk of retinal detachment.Further, there is a need in the art for a reduction or elimination ofthe need for a cycloplegic agent to be used with aceclidine as well asfor means of storage of stable aceclidine compositions, that preferablyenhance both distance and near depth of focus allowing pupil miosis to a1.50 to 2.0 mm range without ciliary side effects.

SUMMARY OF THE INVENTION

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist, wherein the muscarinic agonist preferentiallyactivates M1 and M3 muscarinic acetylcholine receptors. In still morepreferred embodiments the muscarinic agonist is more highly selectivefor M1 than M3. In certain embodiments, the present invention isdirected to compositions and methods for the treatment of presbyopiacomprising a muscarinic agonist that preferentially activates M1 and M3muscarinic acetylcholine receptors.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist selected from the group consisting of aceclidine,talsaclidine, sabcomeline, cevimeline, WAY-132983, AFB267B (NGX267),AC-42, AC-260584, 77-LH-28-1, and LY593039 or any pharmaceuticallyacceptable salts, esters, analogues, prodrugs or derivatives thereof.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist that activates only M1 muscarinic acetylcholinereceptors.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine.

In certain preferred embodiments, the present invention is directed toophthalmological compositions for the treatment of presbyopia comprisingaceclidine, preferably at a concentration from about 0.25% to about 2.0%w/v, and a cycloplegic agent, preferably tropicamide.

In certain preferred embodiments, the present invention is directedophthalmological compositions for the treatment of presbyopia comprisingaceclidine, preferably at a concentration from about 0.25% to about 2.0%w/v and a polyol, preferably mannitol at a concentration from about 1.0%to about 10.0% w/v, more preferably 2.5% w/v.

In certain preferred embodiments, the present invention is directedophthalmological compositions for the treatment of presbyopia comprisingaceclidine, preferably at a concentration from about 0.25% to about 2.0%w/v, a polyol, preferably mannitol at a concentration from about 1.0% toabout 10.0% w/v, more preferably 2.5% w/v and tropicamide, preferably ata concentration from about 0.004% to about 0.08% w/v, more preferablyfrom about 0.004% to about 0.049% w/v and most preferably from about0.004% to about 0.025% w/v.

In certain preferred embodiments, the present invention is directedophthalmological compositions for the treatment of presbyopia comprisingaceclidine, preferably at a concentration from about 0.25% to about 2.0%w/v, a polyol, preferably mannitol at a concentration from about 1.0% toabout 10.0% w/v, more preferably 2.5% w/v, and a nonionic surfactant,preferably the nonionic surfactant is selected from the group consistingof a polysorbate, a polyoxyl castor oil, a polyoxyl stearate, apoloxamer, a polyethylene glycol, a polyoxyethylene glycol alkyl ether,tyloxapol and2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol,more preferably polysorbate 80 or polyoxyl 35 castor oil, morepreferably at a concentration of about 0.5% to about 10.0% w/v, morepreferably from about 1.0% to about 7.0% w/v, even more preferably about2.5% or 3.5% w/v.

In certain preferred embodiments, the present invention is directedophthalmological compositions for the treatment of presbyopia comprisingaceclidine, preferably at a concentration from about 0.25% to about 2.0%w/v, more preferably 1.75% w/v, a polyol, preferably mannitol at aconcentration from about 1.0% to about 10.0% w/v, more preferably 2.5%w/v, tropicamide, preferably at a concentration from about 0.004% toabout 0.025% w/v, more preferably about 0.005% to about 0.007%, anonionic surfactant, preferably polysorbate 80, more preferably at aconcentration of about 0.5% to about 10.0% w/v, more preferably fromabout 2.0% to about 6.0% w/v, even more preferably about 2.5% to about4.0% w/v and a viscosity enhancer, preferably selected from the groupconsisting of a cellulose derivative, hyaluronate, a carbomer and a gum,more preferably high molecular weight carboxymethyl cellulose orcarbomer 940, preferably at a concentration from about 1.0% to about2.0% w/v, and more preferably about 1.35% to 1.45% w/v and even morepreferably about 1.42% w/v, or other viscosity agent such ashydroxypropylmethyl cellulose, preferably at a concentration from about1.0% to about 2.0%, and more preferably about 1.75% or 1.80%, whereininitial viscosity of the composition prior to instillation in the eyemay range from about 25 to about 10,000 centipoise, and more preferablyabout 100 to about 5000 centipoise and may be non-Newtonian with minimalblur at high shear (intrablink) vs. low shear (between blinks) afterinstillation.

In certain preferred embodiments, the present invention is directedophthalmological compositions for the treatment of presbyopia comprisingaceclidine, preferably at a concentration from about 0.25% to about 2.0%w/v, more preferably 1.75% w/v, a polyol, preferably mannitol at aconcentration from about 1.0% to about 10.0% w/v, more preferably 2.5%w/v, tropicamide, preferably at a concentration from about 0.004% toabout 0.025% w/v, more preferably about 0.005% to about 0.007%, anonionic surfactant, preferably polysorbate 80, more preferably at aconcentration of about 0.5% to about 10.0% w/v, more preferably fromabout 2.0% to about 6.0% w/v, even more preferably about 2.5% to about4.0% w/v, a viscosity enhancer, preferably selected from the groupconsisting of a cellulose derivative, hyaluronate, carbomer 940 and agum, more preferably high molecular weight carboxymethyl cellulose orcarbomer 940, preferably at a concentration from about 1.0% to about2.0% w/v, and more preferably about 1.35% to 1.45% w/v and even morepreferably about 1.42% w/v, or other viscosity agent such ashydroxypropylmethyl cellulose, preferably at a concentration from about1.0% to about 2.0%, and more preferably about 1.75% or 1.80%, whereininitial viscosity of the composition prior to instillation in the eyemay range from about 25 to about 10,000 centipoise, and more preferablyabout 100 to about 5000 centipoise and may be non-Newtonian with minimalblur at high shear (intrablink) vs. low shear (between blinks) afterinstillation, and a preservative, preferably selected from the groupconsisting of benzalkonium chloride (“BAK”), sorbic acid and oxychlorocomplex.

In certain more preferred embodiments, the present invention is directedto ophthalmological compositions for the treatment of presbyopiacomprising about 1.65% to about 1.8% aceclidine and about 2.0% to about3.0% w/v polyol.

In certain other more preferred embodiments the present invention isdirected to ophthalmological compositions for the treatment ofpresbyopia comprising about 1.65% to about 1.8% aceclidine, about 2.0%to about 3.0% w/v polyol and about 2.0% to about 6.0% w/v nonionicsurfactant.

In certain other more preferred embodiments the present invention isdirected to ophthalmological compositions for the treatment ofpresbyopia comprising about 1.65% to about 1.8% aceclidine, about 2.0%to about 3.0% w/v polyol, about 2.0% to about 6.0% w/v nonionicsurfactant and about 0.5% to about 2.0% w/v viscosity enhancer.

In certain more preferred embodiments, the present invention is directedto ophthalmological compositions for the treatment of presbyopiacomprising about 1.65% to about 1.8% aceclidine, about 2.0% to about3.0% w/v polyol and about 0.004% to about 0.025% w/v of a cycloplegicagent.

In certain more preferred embodiments, the present invention is directedto ophthalmological compositions for the treatment of presbyopiacomprising about 1.75% w/v aceclidine, about 2.5% w/v polyol, about2.75% w/v polysorbate 80, and about 1.80% w/v hydroxypropylmethylcellulose, and where hydroxypropylmethyl cellulose may in allformulations be substituted for about 1.25% to about 1.45% highmolecular weight carboxymethyl cellulose.

In certain more preferred embodiments, the present invention is directedto ophthalmological compositions for the treatment of presbyopiacomprising about 1.75% w/v aceclidine, about 0.004% to about 0.007% w/vtropicamide, about 2.75% w/v polyol, about 2.5% w/v polysorbate 80, andabout 1.25% to 1.45% w/v carboxymethyl cellulose, or 1.80% w/vhydroxypropylmethyl cellulose.

In certain other embodiments, the present invention is directed to amethod of treating presbyopia comprising administering to a subject inneed thereof a composition of the present invention.

In certain other embodiments, the present invention is directed to amethod of treating presbyopia comprising administering to a subject inneed thereof an ophthalmological composition of the present invention,wherein near vision acuity of the subject is improved by about 3 linesof resolution or more for at least 6 hours.

A method of treating a refractive error of the eye in a subject in needthereof comprising administering to a subject in need thereof apharmaceutically acceptable amount of a composition of the presentinvention wherein the refractive error of the eye is selected frompresbyopia, myopia, hyperopia, astigmatism or a combination thereof.

The present invention is further directed to a method for treatingpresbyopia comprising administering to a patient in need thereof acomposition of the present invention.

A method for treating a refractive error of the eye comprisingadministering to a patient in need thereof a pharmaceutically acceptableamount of a composition of the present invention, wherein the size ofthe pupil is reduced to from about 1.5 to about 2.5 millimeters,preferably from about 1.7 to about 2.2 millimeters and wherein therefractive error is selected from the group consisting of a range ofdistance corrected vision for mild to moderate hyperopia of 3.0 D orless; mild to moderate myopia of −5.0 D or less; regular astigmatism of3.0 D or less; uncorrected distance vision for emmetropes of +0.50 to−0.50 spheq with regular astigmatism of 0.75 D or less; cornealirregular astigmatism, an ectasia induced corneal irregularity, apellucid induced corneal irregularity, a higher order aberration and arefractive surgery induced higher order aberration.

The present invention is further directed to a method of increasing thevisual depth of field (i.e. depth of focus) secondary to pupil miosis,comprising administering to a subject in need thereof a pharmaceuticallyeffective amount of an ophthalmological composition of the presentinvention.

The present invention is further directed to a method of reducing theside effects of ophthalmic aceclidine administration by modulating theagonist effect on the ciliary body of the eye such that ciliary spasm,ciliary induced brow ache, and/or ciliary induced headache aresubstantially reduced or eliminated.

The present invention is further directed to a method of allowingbinocular physiologic topical presbyopic correction.

The present invention is further directed to a method of eliminating theneed for monocular limitation due to distance blur, or reduced totreatment of mild hyperopes to counteract induced myopic blur, astypically associated with pilocarpine, or pilocarpine and alpha agonistcombinations.

The present invention is further directed to a method of improving nearvision by increasing accommodation without reduction in distance visionsharpness. This is achieved by simultaneously increasing incrementalaccommodation, modulated so that while sufficient to provide additivenear vision enhancement, it remains at a rate of induction and totaldegree of accommodation such that the associated myopic blur does notbreak through the ability of the simultaneously induced pupil miosispinhole effect to filter the refractive error and maintain distancesharpness.

The present invention is further directed to a method of increasing thevisual depth perception upon improving near vision unaided comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of an ophthalmological composition of the present invention inboth eyes (binocular vision), wherein such binocularity further enhancesnear vision beyond that of either eye separately.

The present invention is further directed to a method of improvingvision in a subject with ammetropia (vision abnormality), comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of a composition of the present invention.

The present invention is further directed to a method of improvingvision in a subject with ammetropia, comprising administering to asubject in need thereof a pharmaceutically effective amount of acomposition of the present invention, wherein ammetropia is selectedfrom the group consisting of nearsightedness, farsightedness, regularastigmatism, irregular astigmatism and high degrees of regularastigmatism.

The present invention is further directed at eliminating opticalaberrations induced by corneal irregularity, opacities, or very highdegrees of regular astigmatism that include regions adjacent orperipheral to the central 1.5 mm optical zone, and thereby inducingimproved visual acuity and quality of vision by filtering out theseaberrant optics in those suffering from irregular astigmatism or highdegrees of more regular astigmatism, such as occurs in conditions suchas keratoconus, photorefractive keratectomy induced corneal haze,diffuse lamellar keratitis (“DLK”) (post-lasik DLK), other iatrogeniccorneal induced irregularity such as cataract incision, glaucomafiltering blebs, implanted glaucoma valves, corneal inlays with orwithout removal, ectasia post corneal surgery (lasik), and secondary toinfection.

The present invention is further directed at improving acuity relativeto existing uncorrected refractive error. Upon this improved acuity,patients now requiring toric contact lenses for astigmatism with reducedcomfort and optics that may shift during each blink may in many casesrequire only non-toric soft contact lenses or no contact lenses.Further, those requiring gas permeable contact lenses may no longerrequire contact lenses or only require much more comfortable softcontact lenses. Patients with high degrees of astigmatism may nowrequire no correction or reduced astigmatic correction. Patients withsmall to moderate degrees of nearsightedness may require less correctionor no longer require correction. Patients with small to moderate degreesof hyperopia (farsightedness) may require no correction or reducedcorrection.

The present invention is directed to methods and ophthalmologicalcompositions for improving eye sight. In a preferred embodiment thepresent invention is directed to methods and ophthalmologicalcompositions for the treatment of presbyopia. In a more preferredembodiment the present invention is directed to ophthalmologicalcompositions comprising aceclidine.

The present invention is directed to methods of treating irregularastigmatism, keratoconic ectasia, and low myopia, or hyperopia, with orwithout astigmatism, comprising administering to a subject in needthereof an ophthalmological composition of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of the effects of pilocarpine andaceclidine with or without tropicamide and with or without a carrier onnear and distance vision in a patient over the age of 45.

FIG. 2 is a graphical representation of the effects of addition ofnon-ionic surfactants and viscosity enhancers on near vision acuity andduration of effect. Line-Hours denotes lines improved times duration ofeffect.

FIG. 3 is a graphical representation of the Efficacy Index for formulas#L33-#L94. Box color denotes a comfort level of good for white, fair forcross-hatched and poor for black.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions and methods oftreating presbyopia, irregular astigmatism, and/or refractive error,comprising administering to a patient in need thereof a pharmaceuticalcomposition comprising a muscarinic agonist that preferentiallyactivates M1 and M3 muscarinic acetylcholine receptors, preferablyactivate M1 more than M3 and most preferably aceclidine or itsderivatives. Aceclidine has been surprisingly and unexpectedlydiscovered to provide enhanced presbyopic reversal with negligible sideeffects day or night (when viewing includes one or more direct orreflected light sources) using compositions of the present invention.

Aceclidine is traditionally used as a treatment for glaucoma. Whenaceclidine is used to treat glaucoma it is normally stored in atwo-bottle system; one bottle containing the lyophilized aceclidine andthe second bottle containing the diluent necessary to reconstitute thelyophilized aceclidine before topical instillation. Romano J. H.,Double-blind cross-over comparison of aceclidine and pilocarpine inopen-angle glaucoma, Brit J Ophthal, August 1970, 54(8), 510-521. It isa further aspect of the present invention to provide an aqueousaceclidine composition that is stable in combination with cold chainstorage. It is yet a further aspect of the present invention to providea method of stabilizing aqueous aceclidine by combining effectiveexcipients, pH ranges and temperature ranges.

The compositions and methods of the present invention treat presbyopiaby improving depth of focus in patients with presbyopia by administeringan ophthalmological composition to the eye that reduces pupil dilationin the dark or in dim light, produces a particular degree and durationof miosis without accommodation, provides cosmetic whitening and/orinduce redness prophylaxis. The compositions and methods of the presentinvention also do not cause significant pupil rebound, tachyphylaxis,ciliary spasms, induction of myopia or reduction in distance vision.Additionally, the compositions and methods of the present inventionallow for the further improvement in visual acuity and depth perceptionof binocular (both eyes) treatment. The ophthalmological composition ofthe present invention surprisingly creates a pupil of from about 1.5 toabout 2.4 mm at the anterior iris plane and about 2.0 mm at the cornealsurface with negligible increase in accommodative tone and with areduction or ablation of the redness that is otherwise a hallmark of theuse of miotic agents. This pupil miosis with greatly diminished orabsent accommodative tone is superior to the pinhole effect of theKamra® and Flexivue Microlens® corneal inlays. Pupil miosis is superiorbecause the constriction of the actual pupil does not result in theattendant severe night vision disturbance caused by the light scatteringborders of the pre-corneal pinholes created by the inlays. Further pupilmiosis provides a greater field of vision and transmission of morefocused light, and in a discovered optimal pupil range of about 1.7 mmto 2.1 mm using formulation discoveries of the present invention does sowith negligible to mild and very tolerable dimming and enhancedcontrast, distance vision, reduced glare at night, and improved nearvision.

The use of aceclidine has a minimal effect on the longitudinal ciliarymuscle, thus reducing risk of retinal detachment when compared to theuse of general muscarinic agonists such as pilocarpine and carbachol.The further inclusion of a cycloplegic agent resulted in only 0.04 mm ofanterior chamber shallowing. Aceclidine, particularly as enhanced forthe present invention, also has greater magnitude, duration, and controlof minimum pupil diameter than conventional pilocarpine with or withoutalpha agonists, and less anterior chamber inflammation with chronic use.Compositions of the present invention achieve these advantages byallowing both pinhole near vision depth perception benefit and modestaccommodative increase below the threshold of induced myopic distanceblur through the miotic pupil, whereby, not wishing to be held toparticular theory, it is believed the rate of miosis and the rate ofaccommodative increase maintain a balance allowing pinhole correction ofotherwise induced accommodative blur. This combination thus is found toavoid the distance blur typically seen in patients as a response topilocarpine and/or carbachol induced miosis without the formulationdiscoveries of the present invention, as well as the excessiveaccommodative myopia and ciliary spasm manifested as brow ache orgeneralized migraine-like headache.

Such conventional formulations of pilocarpine, in order to effect anyreasonable duration of effect, are still restricted to less than orequal to about 4 hours in most cases, as the high ratio of accommodationto pupillary miosis requires minimal concentrations of pilocarpine ofabout 1.0% to minimize but not eliminate distance induced myopic blurand ciliary spasm. Further pilocarpine must be instilled monocularly tominimize intolerable distance blur to a still bothersome 2-3 lines ofdistance blur. Even instilled monocularly, pilocarpine still may createbothersome attendant distance blur and must be restricted to about 1.0%.Upon instillation of 1.0% pilocarpine pupil size is about 2.3 mm orlarger in most subjects and thereby restricts any significant pinholedepth perception benefit as well as any pinhole filtering of inducedmyopic rays. The restriction to about 1.0% for these conventionalformulations of pilocarpine with the attendant short duration and stillbothersome but reduced distance blur in emmetropes or myopes (somewhatneutralized in low hyperopes) are attempts to prevent extremely strongaccommodation of 5D to 11 D well known to occur at higher concentrationsof pilocarpine.

Any effects on accommodation may be further reduced or totallyeliminated in preferred embodiments by combining a miotic with acycloplegic agent in a narrow and particular ratio of miotic tocycloplegic, where such ratios as discovered for U.S. Pat. No.9,089,562, such as about 35:1 for a preferred embodiment, become greatlyincreased for the present invention in the presence of cryoprecipitantas to a factor of about 300%-700%. Aceclidine is capable of producingthe increased depth of focus by both pupil miosis below 2.3 mm andmodest accommodation described in the present invention. Particularlyenhanced miosis occurs with use of compositions of the presentinvention. This enhanced miosis makes it possible to use an α-2 agonistat very low concentrations if desired to reduce mild eye redness. Othercombinations of inactive ingredients reduce or effectively eliminateinduced redness without such agonists. Further, due to the apparent andsurprisingly selective nature of aceclidine, and the commercially stableaceclidine formulation discoveries of the present invention,administration to the eye of compositions of the present inventionresult in a net strongly enhanced near vision acuity from both pupilmiotic pinhole effect and moderate modulated ciliary accommodation.These beneficial effects are accompanied by a filtering pupil effect,which eliminates any distance blur from the accommodation, correctingresidual refractive error and optical aberrations as may exist to inmany cases improve distance vision as well. Thus, the administration ofaceclidine results in pupil miosis without excessive accommodation andattendant distance blur. However, aceclidine alone may cause substantialredness and brow ache. Without formulation enhancement of the presentinvention such as requiring cycloplegic agent, cryoprecipitant or both,aceclidine may produce either less than optimal pupil miosis at lowconcentrations or at higher concentrations require more than desiredpeak miosis to attain satisfactory duration of greater than 3-4 hours.However the use of a cycloplegic agent has been found to be highlysensitive to other inactive ingredients in the formulation not usuallyassociated with effects on active agents, and particularly forcryoprecipitants as found to be preferred commercially for aceclidinereduce or eliminate the need for this cycloplegic requirement toextremely low concentrations in a preferred embodiment, rendering 0.042%sufficiently high when cryoprecipitant is present (e.g. a polyol such asmannitol) to cause substantial loss of efficacy. Further, aceclidinewithout formulation enhancements of the present invention causes dimmingof vision in dim or absent lighting as well as ciliary pain above areasonably tolerable threshold that may last for an hour or more and besimilar to a severe migraine headache.

Certain embodiments of the present invention enhance the discoveredpreferred degree of pupillary miosis by providing a consistent range ofeffect of about 1.50-2.20 mm for most patients using a preferredembodiment of a nonionic surfactant and viscosity enhancer. Similarbenefit may be achieved using other permeation enhancers, particularlyhydroxypropylmethyl cellulose, high viscosity carboxymethyl cellulose,Carbopol® (polyacrylic acid or carbomer), and various viscosityadditives that increase drug residence time, such as xanthan gums, guargum, alginate, and other in situ gels well known to experts in the art.The present invention further prevents nasal congestion otherwiseoccurring when substantial aceclidine levels reach the nasal mucosa, dueto the rheologic properties of the preferred embodiment.

The combination of aceclidine and a low concentration of a selective α-2adrenergic receptor agonist (α-2 agonist or α-2 adrenergic agonist),such as fadolmidine, brimonidine or guanfacine, allows for the desiredmiotic effect with diminished or no redness. The use of lowconcentrations of a selective α-2 agonist results in substantialreduction of hyperemia with greatly reduced risk of rebound hyperemiathat is found in concentrations of about 0.06% w/v or more. Furthermore,the use of low concentrations of selective α-2 agonist does notadversely modify the pupil constriction caused by aceclidine. Incontrast, the use of brimonidine 0.20% w/v, when topically applied forpupil modulation for night vision, result in tachyphylaxis of pupilmodulation due to α-2 receptor upregulation in almost 100% of treatedsubjects within four weeks of use.

Unexpectedly, the addition of a cycloplegic agent results in reductionof any brow ache or associated discomfort by further reducing the degreeof ciliary spasms on topical instillation without impairing the mioticresponse. More unexpectedly and surprisingly, the ratio of 1.40%aceclidine to about 0.040% tropicamide in a preferred embodiment of U.S.Pat. No. 9,089,562 (35:1) becomes about 1.75% aceclidine to about 0.004%to 0.010% tropicamide (350:1, 175:1 respectively) in the presence ofmannitol, where 2.5% provides better effect than 4.0%.

The lack of impairment of the miotic response is an unexpectedsurprising discovery, as particular cycloplegic agents, such astropicamide, have known pupil dilating effects at concentrations as lowas 0.01% w/v (Grunberger J. et al., The pupillary response test as amethod to differentiate various types of dementia, Neuropsychiatr, 2009,23(1), pg 57). More specifically cycloplegic agents cause pupilmydriasis (i.e. dilation of the radial muscle of the iris). Further, theaddition of a cycloplegic agent to the miotic agent unexpectedlyincreases the time at which the pupil maintains the desired size rangewithout becoming too restricted. Peak miotic effect at 30-60 minutes canbe titrated in inverse relation to the cycloplegic concentration. Theconcentrations of tropicamide discovered in the present inventionapparently cause more relaxation of the ciliary muscle than the irisradial musculature. In fact, iris mydriasis is discovered to besuppressed by the addition of tropicamide to compositions containingconcentrations of aceclidine used in the present invention, with insteada more consistent level of miosis for the duration of the miotic effect.Additionally and quite surprisingly, unexpectedly, and beneficially theaddition of tropicamide can reduce the degree of peak pupil miosiswithout inducing mydriasis thereby creating a more constant and idealpupil size throughout the drug induced miosis. This more consistentpupil size allows for beneficial near and distance vision without theadverse dimming or loss of resolution due to diffraction limits at thevery reduced pupil sizes seen at peak pupil miosis (e.g. 1.25 mm).

Previously, in U.S. Pat. No. 9,089,562, it was surprisingly found thatthe addition of at least 0.04% w/v cycloplegic agent resulted in anabatement of ciliary side effects caused by the administration ofaceclidine (1.40%) to the eye, in a preferred embodiment, but suchformulations are not as constituted sufficiently stable for commercialuse.

Several additional discoveries of the present invention allow forcommercially stable aceclidine formulations:

-   -   a. Equally or more surprising than the synergistic effects of        cyloplegics of 0.040% added to aceclidine 1.40%, is the        discovery of the present invention that combination of        aceclidine 1.50%-2.0%, and preferably about 1.75% and a polyol,        in a preferred embodiment mannitol, particularly at 0.5% to 4.0%        and most preferably about 2.5%, can achieve a similar pupil        range with reduced or absent ciliary side effects. The polyol        when combined with aceclidine can then be combined to allow        lyophilization without degradation of aceclidine and        simultaneously further reduce or eliminate the need for a        cycloplegic agent for the present invention vs. the teachings of        cycloplegic concentration ranges required in U.S. Pat. No.        9,089,562. Optionally, the addition of a polyol can therefore        also be used to greatly reduce (i.e. no more than 0.025% w/v        cycloplegic agent, preferably 0.004% to 0.015% and most        preferably 0.005% to 0.010%) the concentration of cycloplegic        required to further eliminate mild, but potentially bothersome,        ciliary side effects particularly in younger presbyopes and        further modulate pupil miosis over aceclidine and polyol        combinations alone, reducing and in most cases eliminating any        bothersome peak concentration dimming, as found in preferred        embodiments of the present invention. In preferred embodiments        it is discovered that aceclidine about 1.50%-2.0% and more        preferably 1.75% and mannitol about 0.5%-4.0% and more        preferably 2.5% provide optimal concentration combinations for        the present invention, that are necessary but not sufficient for        about 3 lines of near improvement and 5 or more hours duration        desired for an effective topical presbyopic composition, where        additional formulation discoveries can further enhance the        desired clinical near improvement magnitude and duration;    -   b. It is surprisingly discovered that adding a viscosity agent        to compositions described in a. above only modestly improves        magnitude and duration, however when first adding a nonionic        surfactant, such as polyoxyl stearate or polysorbate 80, optimal        concentrations are discovered that provide greatly improved        magnitude and duration for the present invention, to which        viscosity may then provide added duration much more        substantially than when added alone. For polysorbate 80 or        polyoxyl 40 stearate concentrations of 1.0% to 10.0%, and more        preferably about 2.5% to 5.0% w/v have been found to be        beneficial;    -   c. When formulation improvements of a. and b. above are        combined, preferred embodiments such as aceclidine 1.75%,        mannitol 2.5%, and polysorbate 80 2.75% result. Viscosity agents        such as high viscosity carboxymethyl cellulose (“CMC”) are        surprisingly discovered to moderately enhance magnitude and        greatly enhance duration, unlike with formulations in a. above        alone. High molecular weight CMC concentrations of 0.75% to        1.75%, and most preferably about 1.40%, or hydroxypropylmethyl        cellulose (“HPMC”) at about 1.50% to 2.0%, and most preferably        about 1.75% or 1.80% when combined result now in about +3 lines        of near vision improvement or greater, at a duration of 5-10        hours, at a mean of about 7 hours or greater vs. pilocarpine        1.0% of about less than 4 hours;    -   d. Buffers such as phosphate or acetate at pH 5.0 to 6.0 is        added in a preferred embodiment; and preservatives such as BAK        at 0.010% or 0.020%, sorbic acid or Purite® (oxycloro complex;        Purite is a registered trademark of Allergan, Inc.) may be added        to a preferred embodiment.    -   e. Additionally 0.5% or 1.5% sodium chloride is added in a        preferred embodiment. Optionally, sodium chloride may be        substituted with boric acid, preferably at 0.35% or potassium        borate, preferably at 0.47%; and    -   f. Not wishing to be held to particular theory, it appears the        addition of nonionic surfactant at optimized concentration of        about 2.5% to 5.0% enhances permeation of aceclidine into the        eye. This increased permeation coincides with the desirable        increase in magnitude and duration and increases in ciliary        sensation and dimming. Therefore in the presence of the combined        formulation enhancements of a-d. above, where a cycloplegic        agent is no longer required for a-d. above, addition of a        nonionic surfactant at concentrations found to be preferred may        be further improved with much lower concentrations of a        cycloplegic agent than those found in U.S. Pat. No. 9,089,562,        such as the use of about 0.042% tropicamide with aceclidine        1.40%. For the present invention then preferred embodiments        include aceclidine of about 1.75%, mannitol 2.5%, polysorbate 80        of about 2.5% to 5.0%, CMC of about 1.42%, or HPMC of about 1.8%        and tropicamide of about 0.004%-0.010%, more preferably about        0.005% to 0.007%, and most preferably about 0.005%-0.006%.        Micelle formation above the critical micellar concentration may        allow for micelles to spread across the tear film surface and        spread at low concentrations to cover this surface, while at        higher concentrations these micelles becoming increasingly        contracted and “squeezed” along the surface. Not wishing to be        held to particular theory, it is believed at an optimal        concentration a minimal micelle diameter is achieved before        significant multiple lamellae (layering) occurs. It is believed        that at the optimal concentration nanomicelles of about 100 to        250 nm along the surface are achieved surrounding the highly        charged and hydrophilic aceclidine, facilitating its penetration        through the very lipophilic epithelium.

General miotic agents, such as pilocarpine, carbachol and phospholinediesterase, are capable of causing pupil miosis resulting in improvednear vision of presbyopic patients. However, there is an inversereduction in distance vision associated with these general miotic agentsfrom miosis at peak effect and accommodation that is not seen withaceclidine. The co-administration of a cycloplegic agent with aceclidinesurprisingly results in an attenuation of this reduction in distancevision.

Comfort, safety, and efficacy of a preferred embodiment of anophthalmological composition of the present invention results from thepresence of a nonionic surfactant, such as cyclodextrin alpha, beta, orgamma chains, preferably 2-hydroxypropyl beta-cyclodextrin (“HPβCD”),and, sulfobutyl ether derivative of β-cyclodextrin (Captisol®), apolyoxyl alkyl such as polyoxyl 40 stearate and polyoxyl 35 castor oil,or a poloxamer such as poloxamer 108 and poloxamer 407, a polysorbatesuch as polysorbate 80 or Brij® 35 (Brij is a registered trademark ofUniqema Americas LLC); a viscosity enhancing agent, such ascarboxymethyl cellulose (“CMC”); a tonicity adjustor, such as sodiumchloride; a preservative, such as benzalkonium chloride and a pH fromabout 5.0 to about 8.0. Further, an increase in the concentration of thenonionic surfactant may result in reduced redness. Specifically,increasing polysorbate from 0.10% to 0.50-1.0% results in reducedredness. Further, increasing CMC or Carbopol® 940 from 0.50% to 1.5% w/v(preferably 1.40-1.43% w/v) results in enhanced near vision, bothquantitative improvement and duration improvement.

The viscosity of compositions of the present invention comprising aviscosity enhancer may be from about 1 to about 10,000 cps prior totopical instillation in the eye. As a result of the shear force appliedto the composition as it exits the device used for administration theviscosity is lowered to a range from about 1 to about 25 cps at the highshear of blinking, and 50 cps to 200 cps at the low shear betweenblinks, allowing greater drop retention with less spillage and lessnasolacrimal drainage and systemic absorption upon topical instillation.

Definitions

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The term “stabilizing”, as used herein, refers to any process whichfacilitates and/or enables an active agent to remain in solution. Theterm “stabilizing”, as used herein, also refers to any means or processwhich inhibits and/or reduces the tendency of a muscarinic agonist,including aceclidine, to degrade.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 5% w/v” is to be understood as“4.5% to 5.5% w/v.” Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

As used herein “% w/v” refers to the percent weight of the totalcomposition.

As used herein the term “subject” refers but is not limited to a personor other animal.

The term muscarinic receptor agonist (“muscarinic agonist”) encompassesagonists that activate muscarinic acetylcholine receptors (“muscarinicreceptors”). Muscarinic receptors are divided into five subtypes namedM1-M5. Muscarinic agonists of the present invention include thosemuscarinic agonists that preferentially activate M1 and M3 receptorsover M2, M4 and M5 receptors (“M1/M3 agonists”). M1/M3 agonists includebut are not limited to aceclidine, xanomeline, talsaclidine,sabcomeline, cevimeline, alvameline, arecoline, milameline, SDZ-210-086,YM-796, RS-86, CDD-0102A(5-[3-ethyl-1,2,4-oxasdiazol-5-yl]-1,4,5,6-tetrahydropyrimidinehydrocholoride), N-arylurea-substituted 3-morpholine arecolines,VUO255-035(N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide),benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B (NGX267),AC-42, AC-260584, chloropyrazines including but not limited to L-687,306, L-689-660, 77-LH-28-1, LY593039, and any quiniclidine ring with oneor more carbon substitutions particularly that include an ester, sulfur,or 5 or 6 carbon ring structure including with substituted nitrogen(s)and or oxygen(s), or any pharmaceutically acceptable salts, esters,analogues, prodrugs or derivatives thereof. A preferred M1/M3 agonist isaceclidine. In a preferred embodiment, muscarinic agonist of the presentinvention include those muscarinic agonist that preferentially activateM1 and M3 over M2, M4, and M5; and even more preferably activate M1 overM3. In a more preferred embodiment muscarinic agonist of the presentinvention include those muscarinic agonists that only activate M1.

The term “aceclidine” encompasses its salts, esters, analogues, prodrugsand derivatives including, but not limited to, aceclidine as a racemicmixture, aceclidine (+) enantiomer, aceclidine (−) enantiomer,aceclidine analogues, including, but not limited to, highly M1 selective1,2,5 thiadiazole substituted analogues like those disclosed in Ward. J.S. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent mlmuscarinic agonists, J Med Chem, 1998 Jan. 29, 41(3), 379-392 andaceclidine prodrugs including but not limited to carbamate esters.

The term “selective α-2 adrenergic receptor agonists” or “α-2 agonist”encompasses all α-2 adrenergic receptor agonists which have a bindingaffinity of 900 fold or greater for α-2 over α-1 adrenergic receptors,or 300 fold or greater for α-2a or α-2b over α-1 adrenergic receptors.The term also encompasses pharmaceutically acceptable salts, esters,prodrugs, and other derivatives of selective α-2 adrenergic receptoragonists.

The term “low concentrations” or “low-dose” of alpha-2 adrenergicreceptor agonists refers to concentrations from between about 0.0001% toabout 0.065% w/v; more preferably, from about 0.001% to about 0.035%w/v; even more preferably, from about 0.01% to about 0.035% w/v; andeven more preferably, from about 0.03% to about 0.035% w/v.

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and Alphagan®.

The terms “treating” and “treatment” refer to reversing, alleviating,inhibiting, or slowing the progress of the disease, disorder, orcondition to which such terms apply, or one or more symptoms of suchdisease, disorder, or condition.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable (i.e. without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner).

As used herein, the term “pharmaceutically effective amount” refers toan amount sufficient to effect a desired biological effect, such as abeneficial result, including, without limitation, prevention,diminution, amelioration or elimination of signs or symptoms of adisease or disorder. Thus, the total amount of each active component ofthe pharmaceutical composition or method is sufficient to show ameaningful subject benefit. Thus, a “pharmaceutically effective amount”will depend upon the context in which it is being administered. Apharmaceutically effective amount may be administered in one or moreprophylactic or therapeutic administrations.

The term “prodrugs” refers to compounds, including, but not limited to,monomers and dimers of the compounds of the invention, which havecleavable groups and become, under physiological conditions, compoundswhich are pharmaceutically active in vivo.

As used herein “salts” refers to those salts which retain the biologicaleffectiveness and properties of the parent compounds and which are notbiologically or otherwise harmful at the dosage administered. Salts ofthe compounds of the present inventions may be prepared from inorganicor organic acids or bases.

The term “higher order aberrations” refers to aberrations in the visualfield selected from starbursts, halos (spherical aberration), doublevision, multiple images, smeared vision, coma and trefoil.

The term “cold chain” refers to storage at temperatures from about 2 toabout 8° C. from manufacture to immediately prior to administration.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids or bases. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq.

The salts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,hyaluronic acid, malic acid, sulphuric acid and phosphoric acid and suchorganic acids as oxalic acid, malic acid, maleic acid, methanosulfonicacid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitablesubstituent.

Compositions of the Invention

In one embodiment, the present invention is directed to anophthalmological composition comprising aceclidine. In a preferredembodiment, aceclidine is at a concentration from about 0.25% to about2.0% w/v, more preferably from about 0.50% to about 1.90% w/v, stillmore preferably from about 1.65% to about 1.85% w/v, and most preferablyabout 1.75% w/v. As aceclidine is a tertiary amine with asymmetry, botha + and − optical isomer exist (where in some studies (+) is more potentand in others it is felt (−) may be more potent). For the aboveconcentrations polarimetry demonstrated an exactly equal ratio of (+)and (−) isomer for these concentrations. Altering this ratio couldtherefore alter this concentration range proportional to a change inratio.

The present invention is further directed to an ophthalmologicalcomposition comprising a muscarinic agonist, preferably a nonionicsurfactant above its critical micellar concentration for thecomposition, and a viscosity enhancing agent; or alternatively an insitu gelling agent. In preferred embodiments the initial viscosity ofthe composition on topical application is above 20 cps, preferably 50cps, and more preferably above 70 cps at low shear (1/s).

Nonionic surfactants suitable for the present invention includecyclodextrins, polyoxyl alkyls, poloxamers or combinations thereof, andmay include in addition combinations with other nonionic surfactantssuch as polysorbates. Preferred embodiments include polyoxyl 40 stearateand optionally Poloxamer 108, Poloxamer 188, Poloxamer 407, Polysorbate20, Polysorbate 80, ionically charged (e.g. anionic) beta-cyclodextrinswith or without a butyrated salt (Captisol®) 2-hydroxypropyl betacyclodextrin (“HPβCD”), alpha cyclodextrins, gamma cyclodextrins,Polyoxyl 35 castor oil, and Polyoxyl 40 hydrogenated castor oil orcombinations thereof. Further, substitution of other nonionicsurfactants compatible with ophthalmological use allows for similarformulation advantages, which may included but is not limited to one ormore of a nonionizing surfactant such as poloxamer, poloxamer 103,poloxamer 123, and poloxamer 124, poloxamer 407, poloxamer 188, andpoloxamer 338, any poloxamer analogue or derivative, polysorbate,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, anypolysorbate analogue or derivative, cyclodextrin,hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomlymethylated β-cyclodextrin, β-cyclodextrin sulfobutyl ether,γ-cyclodextrin sulfobutyl ether or glucosyl-β-cyclodextrin, anycyclodextrin analogue or derivative, polyoxyethylene, polyoxypropyleneglycol, an polysorbate analogue or derivative, polyoxyethylenehydrogenated castor oil 60, polyoxyethylene (200), polyoxypropyleneglycol (70), polyoxyethylene hydrogenated castor oil, polyoxyethylenehydrogenated castor oil 60, polyoxyl, polyoxyl stearate, nonoxynol,octyphenol ethoxylates, nonyl phenol ethoxylates, capryols, lauroglycol,polyethylene glycol (“PEG”), Brij® 35, 78, 98, 700 (polyoxyethyleneglycol alkyl ethers), glyceryl laurate, lauryl glucoside, decylglucoside, or cetyl alcohol; or zwitterion surfactants such as palmitoylcarnitine, cocamide DEA, cocamide DEA derivatives cocamidopropylbetaine, or trimethyl glycine betaine, N-2(2-acetamido)-2-aminoethanesulfonic acid (ACES), N-2-acetamido iminodiacetic acid (ADA),N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonic acid (BES),2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol(Bis-Tris), 3-cyclohexylamino-1-propane sulfonic acid (CAPS),2-cyclohexylamino-1-ethane sulfonic acid (CHES),N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropane sulfonic acid (DIPSO),4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid (EPPS),N-2-hydroxyethylpiperazine-N′-2-ethane sulfonic acid (HEPES),2-(N-morpholino)-ethane sulfonic acid (MES), 4-(N-morpholino)-butanesulfonic acid (MOBS), 2-(N-morpholino)-propane sulfonic acid (MOPS),3-morpholino-2-hydroxypropanesulfonic acid (MOPSO),1,4-piperazine-bis-(ethane sulfonic acid) (PIPES),piperazine-N,N′-bis(2-hydroxypropane sulfonic acid) (POPSO),N-tris(hydroxymethyl)methyl-2-aminopropane sulfonic acid (TAPS),N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropane sulfonic acid(TAPSO), N-tris(hydroxymethyl)methyl-2-aminoethane sulfonic acid (TES),2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris), tyloxapol, Solulan™C-24(2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol)and Span® 20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, and sorbitan monooleate). In certain embodiments theaddition of an anionic surfactant such as sodium lauryl sulfate and orsodium ester lauryl sulfate may be preferred. In other embodiments theaddition of polysorbate 80 is preferred. In addition to the abovenonionic surfactants any nonionic surfactant is suitable for use in thepresent invention as long as the concentration of the nonionicsurfactant is such that it is above the critical micellar concentrationfor that non-ionic surfactant. Preferably, the nonionic surfactants usedin the present invention achieve submicron diameter micelles, morepreferably less than 200 nanometers and more preferably less than 150nanometers in diameter.

Ophthalmological in situ gels which may be substituted for or added inaddition to one or more nonionic surfactants include but are not limitedto gelatin, carbomers of various molecular weights including carbomer934 P and 974 P, xanthan gums, alginic acid (alginate), guar gums,locust bean gum, chitosan, pectins and other gelling agents well knownto experts in the art.

In preferred embodiments the nonionic surfactant is polyoxyl 40 stearateat a concentration from about 1 to about 15% w/v, more preferably atabout 5.5% w/v.

In such preferred embodiment, polyoxyl 40 stearate is found to enhancethe redness reduction effect preferentially over aqueous solutions andother nonionic surfactants such as poloxamer 407, particularly in thepresence of an α-2 agonist.

In other preferred embodiments, the nonionic surfactant is polysorbate80 at a concentration from about 0.5% to about 10% w/v, more preferablyfrom about 1% to about 7% w/v and even more preferably from about 2% toabout 5% w/v, yet more preferably from about 2.5% to about 4% w/v andmost preferably at about 2.5% or 2.75% or 3% or 5% w/v.

Viscosity enhancers suitable for the present invention include, but arenot limited to gums such as guar gum, hydroxypropyl-guar (“hp-guar”),and xanthan gum, alginate, chitosan, gelrite, hyauluronic acid, dextran,Carbopol® (polyacrylic acid or carbomer) including Carbopol® 900 seriesincluding Carbopol® 940 (carbomer 940), Carbopol® 910 (carbomer 910) andCarbopol® 934 (carbomer 934), cellulose derivatives such ascarboxymethyl cellulose (“CMC”), methylcellulose, methyl cellulose 4000,hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethylcellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, gellan,carrageenan, alignic acid, carboxyvinyl polymer or combinations thereof.

In a preferred embodiment the viscosity enhancer will have anequilibration viscosity less than 100 cps, preferably from about 15 toabout 35 cps, and most preferably at about 30 cps. In a preferredembodiment the viscosity enhancer is Carbopol® 940 (carbomer 940) at aconcentration from about 0.05% to about 1.5% w/v, preferably from about0.09% to about 1.0% w/v, more preferably at 0.09%, 0.25%, 0.5%, 0.75%,0.9% or 1.0% w/v. In certain combinations it has been surprisinglydiscovered nonionic surfactant/viscosity combinations may result inphase separation over time with precipitate formation. In suchsituations, particularly for polyoxyls, in a preferred embodimentpolyoxyl 40 stearate, and cellulose derivatives, particularlyhydroxypropylmethyl cellulose, use of a nonpolysaccharide derivative forviscosity enhancement, such as polyacrylic acid derivatives (carbomers,carbomer 934 or 940 in preferred embodiments) may prevent suchseparation; or alternatively use of a non polyoxyl nonionic surfactant,such as polysorbate 80 with either a cellulose derivative ornoncellulose derivative viscosity agent may be substituted.

In another preferred embodiment, the viscosity enhancer is carboxymethylcellulose at a concentration from about 1% to about 2% w/v, morepreferably from 1.35% to about 1.45% w/v and most preferably 1.42% w/vor 1.40% w/v.

In another preferred embodiment, the viscosity enhancer ishydroxypropylmethyl cellulose at a concentration from about 1% to about2% w/v, more preferably 1.5% to about 1.90% w/v, even more preferablyfrom about 1.65% to about 1.85% w/v and most preferably 1.75% w/v or1.80% w/v.

Not wishing to be held to particularly theory, it appears thequinuclidine nucleus of the heterocyclic nitrogen on aceclidine is soelectron rich it easily attacks surrounding compounds as well as itself.

It is a discovery of the present invention that several modificationsmay singly or in combination be used to enhance cold chain stabilitystorage, including in addition to in a preferred embodiment aceclidine1.40%-1.75%, tropicamide 0.025%-0.10% and optionally a nonioinicsurfactant such as polyoxyl 40 stearate 0.5%-10%, preferably 5.5% one ormore of (See Table 1):

Acidic pH, preferably less than 5.5, preferably less than 5.0 and mostpreferably at a pH of about 4.75;

Viscosity enhancer, preferably at 25 C viscosity of about 15-50 cps, andmore preferably 20-45 cps, where a preferred embodiment is carbomer 9400.09%-1.5%;

Addition of a polyol, in a preferred embodiment Mannitol 2.5%-4.0%;

Addition of a buffer, where acetate or phosphate buffers are preferred,2-100 mmole range with 3-5 mmole is preferred; and

Addition of a preservative, where BAK 0.015% is preferred.

The selective α-2 agonist may be included within the composition of thepresent invention or applied topically preferably just minutes before orless preferably just minutes afterward if additional means to reducenasal congestion or redness is desired for sensitive subjects. Selectiveα-2 agonists suitable for the present invention have minimal α-1 agonistactivity at low concentrations. For example, for brimonidine orfadolmidine, 1% to 2% w/v is considered extremely high, 0.5% to 1.0% w/vstill highly inductive of α-1 receptors and toxic for purposes of thepresent invention. Further, 0.10% to 0.5% w/v is still too high and even0.070% to 0.10% w/v is associated with a higher than preferred incidenceof rebound hyperemia (however, for dexmedetomidine, its greaterlipophilicity and intraocular penetration reduces rebound risk in thisrange). Only 0.065% w/v or below is potentially acceptable, where formost α-2 agonists, depending on degree of selectivity 0.050% w/v or evenmore preferably 0.035% w/v or less is desired. On the other hand somedegree of useful activity may occur at one or more orders of magnitudefurther reduction of concentration. The preferred embodiments,brimonidine, fadolmidine and guanfacine, of the present inventionpreferentially stimulate α-2 adrenergic receptors, and even morepreferably α-2b adrenergic receptors so that α-1 adrenergic receptorsare not stimulated sufficiently enough to cause excessive large vesselarteriolar constriction and vasoconstrictive ischemia. In addition, ithas been discovered that preventing or reducing redness for drugs thatotherwise directly induce redness, such as the acetylcholine agonist,aceclidine, enhances compliance for sensitive subjects that may haveinduced redness or nasal congestion even with formulations of thepresent invention that do not include an α-2 agonist. However, becauseα-2 agonists are shifted to their ionized equilibrium an acidic pH issomewhat offset by the fact such agonists exert greater affect atneutral or alkaline pH. Therefore each α-2 agonist has a preferred pHrange depending on its lipophilicity and pKa value when added to theinventive compositions with aceclidine. For the present invention whilepH range of 5.0 to 8.0 is tolerated, preferred embodiments are at pH 5.5to 7.5 and more preferably 6.5 to 7.0. Further, it has been discoveredthat cyclodextrins and/or polyoxyl 40 stearate as a nonionic surfactantcomponent or as the sole nonionic surfactant, result in a greaterwhitening effect when the α-2 agonist is included in the compositionrather than poloxamer 407. The α-2 agonist may optionally be appliedseparately or in certain preferred embodiments with formulations of thepresent invention that do not include an α-2 agonist, such as thoseformulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic surfactant,although the α-2 agonist is not required except for occasional sensitivesubjects. Fadolmidine represents the α-2 agonist with highesthydrophilicity and therefore high surface retention for the presentinvention. Guanfacine is also highly selective and hydrophilic.Brimonidine is highly selective with moderate lipophilicity. Finally,dexmedetomidine has high selectivity with high lipophilicity that may beused with less efficacy for reducing redness for the purposes of thepresent invention (although possibly inducing fatigue as a side effectin some patients). In a preferred embodiment using polyoxyl 40 stearate5.5% w/v; CMC 0.80% w/v; NaCl 0.037% w/v; ethylenediaminetetraaceticacid (“EDTA”) 0.015% w/v, borate buffer 5 mM and BAK 0.007% w/v resultsin redness of about 1.0 to 1.5 out of 4 which is transient lasting aboutten minutes, and by 30 minutes returns to about baseline.

In one embodiment, the selective α-2 adrenergic receptor agonist is acompound which has binding affinity of about 900 fold or greater, evenmore preferably about 1000 fold or greater, and most preferably, about1500 fold or greater.

The selective α-2 adrenergic receptor agonist may be present at aconcentration from between about 0.0001% to about 0.065% w/v; morepreferably, from about 0.001% to about 0.035% w/v; even more preferably,from about 0.01% to about 0.035% w/v; and even more preferably, fromabout 0.020% to about 0.035% w/v.

In one embodiment, the selective α-2 adrenergic receptor is selectedfrom the group consisting of brimonidine, guanfacine, fadolmidine,dexmedetomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.Analogues of these compounds that function as highly selective α-2agonists may also be used in compositions and methods of the presentinvention.

In a more preferred embodiment, the selective α-2 agonist is selectedfrom the group consisting of fadolmidine, guanfacine and brimonidine. Ina yet more preferred embodiment the selective α-2 agonist is brimonidinein the form of a salt at a concentration of 0.025% to 0.065% w/v, morepreferably from 0.03% to 0.035% w/v. In a preferred embodiment, the saltis a tartrate salt.

In another yet more preferred embodiment, the selective α-2 agonist isfadolmidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.02% to about 0.035% w/v in the form of ahydrochloride (“HCl”) salt.

In another yet more preferred embodiment, the selective α-2 agonist isguanfacine at a concentration from about 0.005% to about 0.05% w/v, morepreferably from 0.02% to about 0.035% w/v in the form of an HCl salt.

In another yet more preferred embodiment, the selective α-2 agonist isdexmedetomidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.04% to about 0.05% w/v in the form of an HClsalt.

In another preferred embodiment a pH less than physiologic pH is foundto enhance the whitening effect for brimonidine, preferably pH 4.5 to6.5, and more preferably pH 5.5 to 6.0. However, redness reduction isachieved at all pHs, and enhancement of aceclidine absorption occurs atalkaline pH, such that more effect occurs from a given concentration,and therefore while effective at pH ranges from 4.5 to 8.0, pH range of6.5 to 7.5 is preferred for the present invention, and 7.0 to 7.5 mostpreferred.

The present invention is further directed to an ophthalmologicalcomposition further comprising a cycloplegic agent. It is a surprisingand totally unexpected discovery of the present invention that certaincycloplegic agents can be combined with miotic agents, particularly forthe present invention, aceclidine, without reducing miotic onset,magnitude, or duration; and further blunt the normally attendant spikein miotic effect coinciding with time of peak absorption in aqueousformulations to provide a constant miosis versus time after onset from15 to 30 minutes to 6 to 10 hours depending on the desired formulation.The addition of the cycloplegic agent also reduces any residualassociated discomfort that may otherwise occur soon after topicalinstillation, which presumably is a result of ciliary spasms orexcessive pupillary miosis.

Cycloplegic agents suitable for the present invention include, but arenot limited to, atropine, Cyclogyl® (cyclopentolate hydrochloride),hyoscine, pirenzepine, tropicamide, atropine,4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin (Vesicare®),tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva),and otenzepad (a.k.a. AF-DX 116 or11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one).In a preferred embodiment the cycloplegic agent is tropicamide at aconcentration from about 0.004% to about 0. 025% w/v, more preferablyfrom about 0.005% to about 0.015% w/v and still more preferably fromabout 0.005% to about 0.011% w/v, from about 0.005% to about 0.007% w/vand from about 0.005% to about 0.006% w/v. In another preferredembodiment the cycloplegic agent is a mixture of tropicamide at aconcentration from about 0.04% to about 0.07% w/v or pirenzepine orotenzepad at a concentration from about 0.002% to about 0.05% w/v.

In a preferred embodiment, tropicamide 0.01% w/v was found to slightlyreduce brow ache, 0.030% w/v to further reduce brow ache and from 0.04%to about 0.07% w/v to completely eliminate brow ache without reductionof the average pupillary miosis diameter over duration of effect.Tropicamide in preferred embodiments has demonstrated completelyunexpected sensitivity of effect, where at about 0.04% w/v unexpectedlyand very effectively reduces or eliminates brow ache and ciliary spasmpain, becoming very noticeably further reduced at 0.042% w/v and absentat 0.044% w/v in a preferred embodiment with no cycloplegia (surprisingdue to its common use as a pupil dilating agent). Yet, tropicamide didnot reduce the mean degree of pupil miosis, the time of onset of pupilmiosis or the subsequent visual benefits. On the contrary, tropicamideblunted the peak miosis seen in aqueous formulations to create a smoothconsistent miotic effect over time. It allowed modulation of peak pupilmiosis to achieve a more even effect over time with no dilation as hasbeen found with its prior use. Specifically, tropicamide is useful toprevent transient constriction below 1.50 mm at 30 to 60 minutesfollowing aceclidine in some embodiments and to reduce transientexcessive and undesirable dimming of vision that may otherwise occur atpeak onset of about 30 minutes. As an example, an ophthalmologicalcomposition comprising 1.53% w/v aceclidine, 5% w/v HPβCD, 0.75% w/vCMC, 0.25% w/v NaCl, 0.01% w/v BAK and a phosphate buffer at pH 7.0; or1.45% w/v aceclidine; 5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC;0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK and 5 mM phosphatebuffer at a pH 7.0; was varied from 0.040% w/v tropicamide, wheremoderate dimming was noted, to 0.044% w/v tropicamide where dimmingbecame almost undetectable other than in extremely dim light conditions.This additional pupil size modulation with a cycloplegic agent allowsaceclidine concentrations sufficient for prolonged effect while bluntingthe attendant peak excessive constriction that is undesirable as well asany uncomfortable brow ache. Surprisingly and due to its short-actingnature, tropicamide achieves this blunting effect without causingmydriasis. Further, in a preferred embodiment, tropicamide 0.014% w/vwas found to reduce brow ache, 0.021% w/v to further reduce brow acheand from 0.028% to 0.060% w/v and in some embodiments up to 0.09% w/v tocompletely eliminate brow ache without cycloplegia (i.e. paralysis ofciliary muscle of the eye).

It has been found for a racemic 50:50 mixture of (+) and (−) aceclidineoptical isomers (where in some studies (+) is more potent and in othersit is felt (−) may be more potent) tropicamide effects may varydepending on the ratio of aceclidine to tropicamide. For example, in anophthalmological composition of the present invention comprising 1.55%w/v aceclidine, 5.5% w/v HPβCD or in a preferred embodiment polyoxyl 40stearate, 0.75% w/v CMC (1%=2,500 centipoise), 0.25% w/v NaCl, and 0.01%w/v BAK and at pH 7.5, 0.042% w/v tropicamide can be differentiated fromeven 0.035% w/v, with the former demonstrating normal indoor nightvision and the latter slight dimming that becomes more noticeable atstill lower concentrations. At higher concentrations, such as from about0.075% to about 0.090% w/v tropicamide, loss of optimal range pupilconstriction 1.50 mm to 1.80 mm range begins, and frank mydriasis athigher concentrations begins to occur. As isomer ratio may alter theeffective concentration, this must be factored into the clinicalefficacy anticipated using aceclidine; for preferred embodiments of thepresent invention a polarimeter was used to determine an exact 50:50isomer ratio was used (personal communication Toronto ResearchChemicals).

FIG. 1 shows the effect of a miotic agent with or without a cycloplegicagent and with or without a carrier. Subject is an emmetrope over theage of 45 with a baseline near vision of 20.100 and baseline distancevision of 20.20. Topical administration to the eye of 1% w/v pilocarpinein saline solution results in an improvement of near vision to 20.40(8a), however this improvement comes at the expense of a reduction indistance vision to 20.100 (8b). The addition of 0.015% w/v tropicamideresults in an improvement of near vision to 20.25 (9a) and a lesseningof the reduction of distance vision to 20.55 (9b), though in certaininstances with some induced irregular astigmatism (mildly blotched areasin reading field of vision). Topical administration of 1.55% w/vaceclidine in saline solution results in an improvement of near visionto 20.40 for an extended time period of 6 hrs (10a) without any effecton the baseline distance vision (10b). 10c and 10d show the effects ofadministering aceclidine in a carrier composed of 5.5% w/v2-hydroxypropyl beta cyclodextrin, 0.75% w/v CMC (1%=2,500 centipoise),0.25% w/v NaCl, and 0.01% w/v BAK. As seen in 10c the carrier increasesthe beneficial effect of aceclidine resulting in better than 20.20 nearvision. As seen in 10d a similar increase in distance vision occurs. 10eand 10f show the effects of adding 0.042% w/v tropicamide to theaceclidine in the carrier. As seen in 10e near vision is improved to20.15 with a quicker onset of maximum visual acuity. As seen in 10f asimilar improvement is seen in distance vision. Taken together, FIG. 1shows that aceclidine is capable of temporarily correcting near visionin a presbyopic subject without affecting the baseline distance vision.Similar results can be achieved with a different miotic agent,pilocarpine, with the addition of a cycloplegic agent such astropicamide. A proper drug carrier can also have a beneficial effect.

The present invention is further directed to an ophthalmologicalcomposition further comprising a tonicity adjustor and a preservative.

A tonicity adjustor can be, without limitation, a salt such as sodiumchloride (“NaCl”), potassium chloride, mannitol or glycerin, or anotherpharmaceutically or ophthalmologically acceptable tonicity adjustor. Incertain embodiments the tonicity adjustor is 0.037% w/v NaCl,

Preservatives that can be used with the present invention include, butare not limited to, benzalkonium chloride (“BAK”), sorbic acid,oxychloro complex, citric acid, chlorobutanol, thimerosal,phenylmercuric acetate, disodium ethylenediaminetetraacetic acid,phenylmercuric nitrate, perborate or benzyl alcohol. In a preferredembodiment the preservative is BAK, sorbic acid, oxychloro complex or acombination thereof. In a yet more preferred embodiment BAK is at aconcentration of about 0.001% to about 1.0% w/v, more preferably at aconcentration of about 0.007%, 0.01% or 0.02% w/v. In another preferredembodiment the preservative is perborate at a concentration of 0.01% toabout 1.0% w/v, more preferably at a concentration of about 0.02% w/v.

Various buffers and means for adjusting pH can be used to prepareophthalmological compositions of the invention. Such buffers include,but are not limited to, acetate buffers, citrate buffers, phosphatebuffers and borate buffers. It is understood that acids or bases can beused to adjust the pH of the composition as needed, preferably of 1 to10 mM concentration, and more preferably about 3 mM or 5 mM. In apreferred embodiment the pH is from about 4.0 to about 8.0, in a morepreferred embodiment the pH is from about 5.0 to about 7.0.

The present invention is further directed to an ophthalmologicalcomposition further comprising an antioxidant. Antioxidants that can beused with the present invention include but are not limited to disodiumethylenediaminetetraacetic acid at a concentration from about 0.005% toabout 0.50% w/v, citrate at a concentration from about 0.01% to about0.3% w/w, dicalcium diethylenetriamine pentaacetic acid (“Ca2DTPA”) at aconcentration from about 0.001% to about 0.2% w/v, preferably about0.01% w/v Ca2DTPA which can be formulated by adding 0.0084% w/v Ca(OH)₂and 0.0032% w/v pentetic acid to the formulation and mixing slowly.Further combinations of antioxidants can be used. Other antioxidantsthat can be used with the present invention include those well known toexperts in the art such as ethylenediaminetetraacetic acid at aconcentration from about 0.0001% to about 0.015% w/v.

It is a surprising and unexpected discovery that topical formulations ofthe present invention, particularly one of the preferred embodimentscomprising aceclidine 1.35% to 1.55% w/v; 5.5% w/v polyoxyl 40 stearate;0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK; and 5mM phosphate buffer at pH 7.0 result in considerably prolonged contactlens wear and comfort after a single topical instillation daily. Thesingle daily use of the preferred embodiments allowed a subject with dryeye to sleep in his lenses for one week periods where previously evenafter a single night vision would be blurred and contact lenses coatedwith film requiring removal and cleaning or replacement (see Example 7).

In preferred embodiments, an ophthalmological composition of the presentinvention comprises aceclidine, a polyol, optionally a cycloplegicagent, a nonionic surfactant at a concentration from about 1% to about5% w/v and a viscosity enhancer at a concentration of about 0.75% toabout 1.6% w/v, preferably about 1.25% to about 1.5% w/v.

The following representative embodiments are provided solely forillustrative purposes and are not meant to limit the invention in anyway.

REPRESENTATIVE EMBODIMENTS

In one embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v; and

mannitol at a concentration of about 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v; and

tropicamide at a concentration of about 0.02% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 5.0% w/v;

carboxymethyl cellulose at a concentration of about 1.4% w/v;

BAK at a concentration of about 0.015% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.5% w/v;

NaCl at a concentration from about 0.10% to about 0.50% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 2.0% w/v;

NaCl at a concentration of about 0.50% w/v

Carbopol® 940 at a concentration of about 1.5% w/v;

BAK at a concentration of about 0.015% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.25.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.25% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v; and

BAK at a concentration of about 0.015% w/v;

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.50% w/v;

NaCl at a concentration of about 0.05% w/v;

boric acid at a concentration of about 0.2% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.2% w/v;

Carbopol® 940 at a concentration of about 0.9% w/v;

BAK at a concentration of about 0.05% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

tropicamide at a concentration of about 0.01% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 5.0% w/v;

CMC at a concentration of about 1.4% w/v;

BAK at a concentration of about 0.015% w/v; and

phosphate buffer at a concentration of about 3 mM,

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

tropicamide at a concentration of about 0.02% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.25% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v; and

BAK at a concentration of about 0.01% w/v.

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

tropicamide at a concentration of about 0.015% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.75% w/v;

NaCl at a concentration of about 0.05% w/v;

boric acid at a concentration of about 0.2% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

phosphate buffer at a concentration of about 3 mM.

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

tropicamide at a concentration of about 0.025% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.2% w/v;

Carbopol® 940 at a concentration of about 0.9% w/v;

BAK at a concentration of about 0.05% w/v; and

phosphate buffer at a concentration of about 3 mM.

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

tropicamide at a concentration of about 0.02% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

Carbopol® 940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

phosphate buffer at a concentration of about 3 mM.

wherein the pH is about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;

tropicamide at a concentration of about 0.040% w/v;

polyoxyl 40 stearate at a concentration of about 5.0% w/v;

mannitol at a concentration of about 2.5% w/v;

acetate or phosphate buffer at a concentration of about 3.0 mM; and

BAK at a concentration of about 0.01% w/v,

wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.55% w/v;

tropicamide at a concentration of about 0.040% w/v;

polyoxyl 40 stearate at a concentration of about 5.0% w/v;

citric acid monohydrate at a concentration of about 0.1% w/v;

mannitol at a concentration of about 4.0% w/v;

Carbopol® 940 at a concentration of 0.09% w/v; and

acetate or phosphate buffer at a concentration of about 3.0 mM;

wherein said composition has a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.50% w/v;

tropicamide at a concentration of about 0.042% w/v;

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

mannitol at a concentration of about 2.5% w/v;

phosphate buffer at a concentration of about 3.0 mM;

Carbopol® 940 at a concentration of about 0.85% w/v; and

BAK at a concentration of about 0.01% w/v,

wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.45% w/v;

tropicamide at a concentration of about 0.042% w/v;

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

citric acid monohydrate at a concentration of about 0.1% w/v;

acetate buffer at a concentration of about 3.0 mM; and

Carbopol® 940 at a concentration of about 0.75% w/v,

wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.45% w/v;

tropicamide at a concentration of about 0.042% w/v;

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

mannitol at a concentration of about 2.0% w/v;

citric acid monohydrate at a concentration of about 0.1% w/v;

phosphate buffer at a concentration of about 3.0 mM; and

Carbopol® 940 at a concentration of about 1.0% w/v,

wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 2.75% w/v polysorbate 80; and

about 1.80% w/v hydroxypropylmethyl cellulose.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 0.005% to about 0.011% tropicamide;

about 2.5% w/v mannitol;

about 2.75% w/v polysorbate 80; and

about 1.80% w/v hydroxypropylmethyl cellulose.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 0.010% w/v tropicamide;

about 2.5% w/v mannitol;

about 5.0% w/v polysorbate 80;

about 1.40% w/v carboxymethyl cellulose high viscosity;

about 3 mM phosphate buffer; and

about 0.010% BAK=as preservative,

with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 0.006% w/v tropicamide;

about 2.5% w/v mannitol;

about 2.5% w/v polysorbate 80;

about 1.75% w/v hydroxypropylmethyl cellulose;

about 3 mM phosphate buffer; and

about 0.020% BAK=as preservative,

with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 0.006% w/v tropicamide;

about 2.5% w/v mannitol;

about 2.5% w/v polysorbate 80;

about 1.75% w/v hydroxypropylmethyl cellulose;

about 3 mM phosphate buffer;

about 0.50% w/v NaCl; and

about 0.020% BAK=as preservative,

with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 3.5% w/v polysorbate 80;

about 1.8% w/v hydroxypropylmethyl cellulose;

about 3 mM phosphate buffer;

about 0.50% w/v NaCl; and

about 0.020% BAK or 0.15% sorbic acid as preservative,

with a pH of about 5.0.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 3.5% w/v polysorbate 80; and

about 1.80% w/v hydroxypropylmethyl cellulose.

In another embodiment, the ophthalmological composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 3.5% w/v polysorbate 80;

about 1.80% w/v hydroxypropylmethyl cellulose; and

one or more excipient selected from the group consisting of about 0.50%w/v sodium chloride, about 0.02% w/v benzalkonium chloride, about 0.10%w/v sorbate, about 0.01% w/v ethylenediaminetetraacetic acid (EDTA) and0.10% w/v citric acid.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.5% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.55% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.6% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.65% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.7% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.75% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.80% w/v, mannitol at a concentrationof 2.75% w/v and Carbopol® 940 at a concentration of 0.09% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.48% w/v, mannitol at a concentrationof 1.5% w/v and Carbopol® 940 at a concentration of 0.50% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.80% w/v, mannitol at a concentrationof 2.5% w/v and Carbopol® 940 at a concentration of 0.9% w/v.

The following Examples are provided solely for illustrative purposes andare not meant to limit the invention in any way.

EXAMPLES Example 1 Effect of Aceclidine on Vision of Subjects Aged 47 to67 Years

Table 1 demonstrates the effect on the near focus ability of presbyopicsubjects before and after ophthalmological administration of acomposition containing aceclidine. Each composition included aceclidinein the concentrations indicated and 5.5% w/v HPβCD, 0.75% w/v CMC, 0.25%w/v NaCl and 0.01% w/v BAK. Additionally compositions administered tosubjects 4 and 5 included 0.125% w/v tropicamide. As aceclidine is anenantiomer, the clinical effectiveness may vary with different ratios.For the present studies a nearly exact 50:50 ratio of stereoisomers wasmeasured as best determined by polarimetry.

TABLE 1 Effects of aceclidine on vision of presbyopic patients. VisionBaseline Post Gtt 15″ Aceclidine R Pre R Post Effect Date # Age % Dist LPre Dist R Pre Near L Pre Near Dist L Post Dist R Post Near L Post Near(h) Aug. 21, 2013 1 67 1.5 20.20 20.30 20.60 20.60 20.20 20.20 20.1520.15 9.00 Aug. 22, 2013 2 52 1.5 20.30 20.30 20.50 20.50 20.25 20.2520.25 20.20 8.00 Aug. 23, 2013 3 61 1.5 20.40 20.30 20.60 20.50 20.2020.25 20.15 20.15 8.00 Aug. 23, 2013 4 61 1.1 20.20 20.25 20.80 20.5020.15 20.15 20.20 20.15 12.00 Aug. 23, 2013 5 53 1.1 20.20 20.20 20.6020.60 20.20 20.20 20.25 20.25 7.00 Aug. 24, 2013 6 47 1.5 20.25 20.2520.100 20.100 20.20 20.20 20.15 20.15 8.00 Aug. 25, 2013 7 58 1.5 20.3020.200 20.100 20.30 20.25 20.30 20.20 20.30 8.00

As seen in Table 1 all subjects had less than perfect near vision(20.20) in both the left and right eye (object at 15 inches from theeye) and most subjects had less than perfect distance vision beforeadministration of the composition. After administration of thecomposition all subjects experienced an improvement in their near visionthat lasted from 7 to 12 hours. Surprisingly, the majority of subjectsalso experienced improvement of their distance vision for the same timeperiod. Still more surprisingly the improvement in near point was muchcloser than 16″ typically required for comfortable reading, in somecases to about 8.5″ more commonly seen in individuals 30 or less. Theaddition of tropicamide, a cycloplegic agent, had no additive ordeleterious effect on vision correction.

Example 2 Effect of Concentration of Concentration of Aceclidine andTropicamide

TABLE 2 Effect of concentration of concentration of aceclidine andtropicamide. #1 #2 #3 #4 #5 (OD) #5 (OS) #6 #7 Brimonidine 0.03% 0.03%0.03% 0.03% 0.03% 0.03% 0.03% Poloxamer 407  5.5% HPBCD  5.5%  5.5% 5.5%  5.5%  5.5%  5.5% 5.5% Aceclidine  1.5%  1.5% 0.75%  1.1%  1.1% 1.1%  1.1% 1.1% Tropicamide 0.014%  0.021%  0.028%  0.042%  0.062% NaCl 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%  CMC 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75%  BAK  0.1%  0.1%  0.1%  0.1%  0.1% 0.1%  0.1% 0.1% Redness (15 m) 3+  1   0.5 0.5 0 0 0 0 Redness (30 m)1.5 0.5 0.25 0.25 0 0 0 0 Brow Ache (60 m) 2+  2+  2 0.5 0.5 0.0 0.0 0.0Stinging (10 m) 2   2   0.5 0 0 0 0 0 BD-OD 20.20 20.20 20.20 20.2020.20 20.20 20.20 20.20 BD-OS 20.25 20.25 20.25 20.25 20.25 20.25 20.2520.25 BN-OD 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt BN-OS 7 pt 7 pt 7 pt7 pt 7 pt 7 pt 7 pt 7 pt BP-photopic 3 mm 3 mm 3 mm 3 mm 3 mm 3 mm 3 mm3 mm BP-mesopic 5 mm 5 mm 5 mm 5 mm 5 mm 5 mm 5 mm 5 mm Miosis start (m)15   15   15 15 15 15 15 15 Miosis (OU) (1 hr) 1.63 mm   1.63 mm  2.0-2.5 mm      1.63 mm   1.63 mm   1.63 mm   1.63 mm   1.70 mm  Distance (OU) (20 m) 20.20 20.20 20.20 20.20 20.20 20.20 20.20 20.20Distance (OD) (1 hr) 20.15 + 2 20.15 + 2 20.20 20.15 + 2 20.15 + 220.15 + 2 20.15 + 2 20.15 + 2 Distance (OS) (1 hr) 20.15 + 2 20.15 + 220.20 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 Disance (OU) (1hr) 20.10 − 3 20.10 − 3 20.15 20.10 − 3 20.10 − 3 20.10 − 3 20.10 − 320.10 − 3 Near (OU) (20 m) 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt Time(hr) 12.5  12.5  6.5 11 10 10 Abbreviations: (C) indicates correctedvision, (m) indicates minutes, (hr) indicates hour, mm indicatesmillimeters, BD indicates baseline distance vision; BN indicatesbaseline near vision, BP indicates baseline pupil size, OD indicatesright eye; OS indicates left eye and OU indicates both eyes. Allpercentages are w/v. “pt” reflects size of print materials, 4 beingequivalent to 20/20 vision and 3 to 20/15 vision. “Time” refers toduration of the effect.

As seen in Table 2 aceclidine at a concentration of at least 1.1% w/vwas able to reduce the size of the pupil to 1.63 mm 1 hour after topicalinstillation resulting in corrected near and distance vision for atleast 10 hours. Lowering of the concentration of aceclidine to 0.75% w/v(formula #3) reduced the miotic effect to 2.0-2.5 mm after 1 hour andvision correction lasted only 6.5 hours. The addition of 0.03% w/vbrimonidine reduced redness of the eye (4 out of 4 without brimonidine,not shown) to 1.5 out of 4 within 30 minutes after topical instillationwhich was maintained for the entire time vision was corrected. Switchingthe nonionic surfactant to HPβCD (formulas #2-6) further reduced theredness of the eye. Lowering of the concentration of aceclidine to 0.75%w/v (formula #3) further reduced eye redness but as mention above alsoreduced the vision correction duration of the formula.

A brow ache and stinging in the eye were noticeable in formulas #1-3with a 2 out of 4 level of pain which was also associated with feelingsof slight nausea, upset stomach and fatigue. Surprisingly, the additionof a cycloplegic agent, tropicamide, reduced brow ache and stinging to0.5 out of 4 and 0 out of 4 respectively with brow ache dissipatingafter 60 minutes (formula #4). Further, the raising of the concentrationof aceclidine to 1.1% w/v restored the longer duration of correctedvision seen in formulas #1-2 without increasing eye redness. However,upon re-topical instillation of formula #4 at the end of the 10 hoursnoticeable brow ache occurred. Topical instillation of formula #5 (OD)and (OS), with increased tropicamide concentrations, following formula#4 relieved the brow ache experienced with re-installation of formula#4. Upon a 3^(rd) topical instillation, at the end of the effectiveduration of formula #5, re-topical instillation of formula #5 again ledto considerable brow ache. Once again, in formula #6, raising theconcentration of tropicamide was able to overcome the brow ache.Additionally and unexpectedly, tropicamide, despite being a cycloplegicagent, had no effect on pupil miosis or vision correction. Surprisingly,the addition of tropicamide resulted in a prolonged duration of optimalpupil size constriction.

To determine the effect of brimonidine on pupil miosis, formula #7, wasadministered. Administration of formula #7 resulted in only a slightdecrease in pupil miosis to 1.70 mm with identical distance and nearvision improvement to that of formula #5. A 2-3+ conjunctival injectionwas noted.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8inches to the horizon at 1.5 hours after installation. A MarcoAutorefractor with infrared camera and superimposed pupil calibrationscale was used for all pupil size measurements. Once an image wasselected it remained on screen allowing accurate calibration.

Example 3 Effect of Concentration of Aceclidine, Brimonidine,Guanfacine, Fadolmidine, Tropicamide and Additives

TABLE 3 Effect of concentration of aceclidine, brimonidine, guanfacine,fadolmidine, tropicamide and additives. AB2T AB4T AB6T AB11T AB12TPROPH13 Aceclidine 1.55 1.55 1.55 1.55 1.85 1.55 Brimonidine 0.037 0.0370.037 0.037 Fadolmidine 0.037 Guanfacine 0.037 HPBCD 5.5 5.5 5.5 5.5 5.55 Tropicamide 0.043 0.043 0.043 0.043 0.042 0.043 CMC* 0.075 0.075 0.0750.075 0.075 0.075 NaCl 0.025 0.025 0.025 0.025 0.025 0.025 BAK 0.01 0.010.01 0.01 0.01 0.01 Glycerin 0.1 0.1 0.1 Poloxamer 188 0.1 0.05 Polyoxyl40 stearate 0.05 pH 6.5 7.5 7.5 7.5 7.0 7.5 nasal congestion 0 0 0 0 0 0stinging initial 0.75 0 1.5 3.5 0 1.5 stinging, 3 min 0.5 0 0 wash out 00 redness initial 0 0 1 D/C 1 1 redness 15 min 0 0 0 D/C 0 0 whitening 00 0 D/C 1.5 1.5 pain 0 0 0 D/C 0 0 vision near 20.30 20.15 20.15 D/C20.15 20.15 vision distance 20.20 20.20 20.20 D/C 20.20 20.20 onset(min) 20 12 16 D/C 12 16 duration (hrs) 5.5 7.5 7.5 D/C 7.5 7.5 colorclear yellow yellow yellow yellow yellow OVERALL 2.5 3.9 3.8 0 4 3.9 *1%= 2,500 cps All percentages are w/v. Scores for nasal congestion,stinging initial, stinging, 3 min, redness initial, redness 15 min,whitening, pain and overall are out of 4. “pt” reflects size of printmaterials, 4 being equivalent to 20/20 vision and 3 to 20/15 vision.Baseline vision was 20.20 both eyes for distance; 20.70 right eyeunaided for near; 20.80 left eye for near (best @ 16″). D/C stands fordiscontinued after eye washing due to intolerable stinging.

Aceclidine at a concentration of 1.55% w/v was able to reduce the sizeof the pupil to about 1.63 mm 30 minutes after topical instillationresulting in corrected near and distance vision to 20.20 or better forat least 6 hours, with noticeable affect lasting about 7.5 hours as seenin Table 3. Lowering of the concentration of aceclidine to 1.25% w/v(not shown) resulted in useful near vision improvement to about20.25-20.30, but not as effective as at the higher dose range alkalinepH resulted in quicker onset, longer duration, and greater effect. Theaddition of 0.037% w/v brimonidine reduced redness of the eye (4 out of4 without brimonidine, not shown) to baseline within 15 minutes aftertopical instillation which was maintained for the about the entire timevision was corrected. Adding glycerin 0.10% w/v noticeably reducedstinging. Adding instead poloxamer 188 0.05% w/v and polyoxyl 40stearate 0.05% w/v however reduced initial stinging further but was moreviscous. The combination of glycerin 0.1% w/v, poloxamer 188 0.1% w/v ata pH of 6.5 was noticeably reduced in onset, duration, comfort andeffectiveness. AB11T did not include glycerin, poloxamer 188, orpolyoxyl 40 stearate, which resulted in substantial stinging anddiscontinuation of the experiment with eye flush irrigation immediatelyafter topical instillation. Substitution of guanfacine 0.037% w/v inAB12T for brimonidine resulted in minimal initial redness with prolongedredness reduction and some degree of whitening, and appeared to provideoverall the best cosmesis though requiring slightly higher aceclidineconcentration for optimal effect.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8to 10 inches to the horizon at 30 minutes after installation for AB4Tand AB6T.

AB4T and AB6T were repeated both monocularly and binocularly.Substantial improvement in depth perception, near point acuity to 3 pt(20.15), and near point distance (8″, 20.20) was noted when both eyeswere treated vs. monocular treatment. Monocular treatment resulted inworsening of vision with both eyes open versus testing only the treatedeye.

Example 4 Effect of Concentration of Aceclidine, Brimonidine,Tropicamide, and Additives

TABLE 4 Effect of concentration of aceclidine, brimonidine, tropicamide,and additives. #8 #9 #10 #11 #12 #13 #14 Aceclidine 1.61% 1.61% 1.61%1.61% 1.61% 1.53% 1.53% Tropicamide 0.042%  0.042%  0.042%  0.042% 0.042%  0.044%  0.044%  Brimonidine 0.042%  0.042%  0.042%  0.042% 0.042%  CMC 0.75% 0.75% 0.80% 0.87% 0.75% 0.75% 0.75% NaCl 0.25% 0.25%0.50% 0.50% 0.25% 0.50% 0.50% BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% pH 7.00 7.00 7.00 7.00 8.00 7.00 7.00 phosphate buffer 5 mM 5 mM 5mM 6 mM 5 mM 5 mM borate buffer 5 mM Onset (min) 15 15 15 15 15 15 15Duration (hrs) 7 7 10-12 10-12 7 9 7 Pupil range (mm) 1.5-1.7 1.5-1.71.5-1.7 1.5-1.7 1.5-1.7 1.8-2.0 1.8-2.0 Dimming 0-4 1.5 1.5 1.5 1.5 1.50.5 0.5 Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.25 0.25 0.25 0.25 0.25 0.000.00 Redness 0-4 0.5 0.5 0.5 0.5 1.5 1.0 0.5 Other watery watery slthicker sl residue watery watery watery Overall 0-5 3.5 3.5 4 4 2.5 4.54.75 #15 #16 #17 #18 #19 #20 #21 Aceclidine 1.53% 1.53% 1.53% 1.53%1.45% 1.65% 1.75% Tropicamide 0.044%  0.044%  0.044%  0.044%  0.042% 0.044%  0.035%  Brimonidine 0.042%  0.042%  0.042%  0.042%  0.042% 0.042%  CMC 0.80% 0.80% 0.80% 0.80% 0.75% 0.75% 0.75% NaCl 0.50% 0.75%0.75% 1.00% 0.25% 0.25% 0.25% BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% pH 7.00 7.00 8.00 7.00 7.00 7.00 8.00 phosphate buffer 5 mM 5 mM 5mM 5 mM 5 mM 5 mM 6 mM borate buffer Onset (min) 15 15 15 15 15 15 15Duration (hrs) 10-12 9 9 7 7 7 7 Pupil range (mm) 1.8-2.0 1.8-2.01.8-2.0 1.8-2.0 1.8-2.1 1.8-2.1 1.8-2.2 Dimming 0-4 0.5 0.5 0.5 0.5 0.50.5 0.5 Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.00 0.00 0.00 0.00 0.00 0.250.00 Redness 0-4 0.5 0.5 1.0 0.5 0.5 0.5 0.5 Other sl thicker sl thickersl thicker thicker watery watery watery Overall 0-5 5 5 5 4 4 4 4

As seen in Table 4, formulas #8-9, an increase in brimonidine to 0.42%w/v resulted in redness reduction to 0.5, while 0.75% w/v CMC resultedin a watery consistency. Unexpectedly, increasing CMC from 0.75% w/v toa range of 0.80% w/v to 0.87% w/v and increasing NaCl from 0.25% w/v to0.75% w/v in formulas #10-11 resulted in a thicker consistency and anincreased residence time from 7 hours to 10-12 hours and decreased theamount of drug that drained into the nasolacrimal duct. This decreaseddrug delivery to the nasal passages results in less nasal congestion.

In formulas #13-18 a decrease in the amount of aceclidine from 1.61% to1.53% w/v resulted in a pupil size range from 1.8-2.0 mm. Dimming as aresult of the restriction of the pupil decreased linearly from 1.5 to0.5 with the decreased amount of aceclidine. Specifically, the 1.8 to2.0 mm pupil created 41% more light than the 1.5 to 1.7 mm pupil.Surprisingly, the 1.8 to 2.0 mm pupil had a near depth increase of 1.75D. This is only a 0.25 D loss from the beneficial 2.00 D seen with the1.5-1.7 mm range. Thus, the 1.80 to 2.0 mm range produces 41% more lightwhile still allowing the full benefit of increased near vision inindividuals under 60 years of age; whereas, individuals 60 years of ageand over still experience total computer benefit and some increased nearbenefit.

The increase in tropicamide concentration from 0.042% w/v (formulas#8-#11) to 0.044% w/v (formulas #13-#18) resulted in a decrease in acheto negligible amounts. The amount of ache may also be correlated withthe age of the individual. For those individuals under the age of 45, anincrease of tropicamide concentration to a range from 0.046% to 0.060%w/v may be preferred.

Further, Table 4 shows an unexpected result seen in formulas #13 and #17where the increase of NaCl from 0.25% w/v to a range of 0.50 to 0.75%w/v resulted in an acceptable redness score of only 1.0 even without theaddition of the redness reducing agent brimonidine.

Formulas #15, #16 and #17 each result in an overall maximum rating of 5by combining the benefits of: (1) reduced aceclidine concentrations toimprove the amount of light produced without significantly affecting thenear vision benefits seen in formulas #8-#12; (2) increased NaClconcentrations resulting in a further reduction in redness even in theabsence of brimonidine; and (3) increased CMC concentrations resultingin longer residency time on the eye.

Formula #19 is an excellent alternative for the minority of individualsthat are high responders to formulas #15-#17 and get noticeable dimmingwith 1.53% w/v aceclidine. Formula #20 is an excellent alternative forthe minority of individuals that are low responders to formula #19.Lastly, Formula #21 is an excellent alternative for the minority ofindividuals that are low responders and get poor pupil response withFormula #20.

Example 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407

TABLE 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407. #22 #23 #24 Aceclidine  1.45%  1.45%  1.45% Tropicamide0.044% 0.044% 0.044% Brimonidine 0.040% 0.040% 0.040% Polyoxyl 40Stearate  5.5% HPβCD  5.5% Poloxamer 407  5.5% CMC  0.80%  0.80%  0.80%NaCl 0.037% 0.037% 0.037% EDTA 0.015% 0.015% 0.015% BAK 0.007% 0.007%0.007% pH 7.00 7.00 7.00 phosphate buffer 5 mM 5 mM 5 mM NasalCongestion 0.00 0.50 1.50 Stinging 0.25 0.25 0.25 Wetting 4.00 4.00 4.00Redness 0.25 0.50 0.50 Visual Blur (<15 sec) 0.50 0.50 1.50 Duration 6-8hrs 6-8 hrs 6-8 hrs Overall 0-4 4.00 4.00 4.00Clinical Protocol

20 presbyopic patients with full distance correction were each given oneof the above formulas (#22-#23). All patients received pre- andpost-drop distance and near acuity measurement, Zeiss Visante® (Visanteis a registered trademark of Carl Zeiss Meditec AG) optical adherencetomography, axial length and contrast acuity testing (i.e.Colenbrander-Michelson 10% Lum target) with the following results:

all patient achieved a miotic pupil of 1.5 to 2.20 mm;

no patient experienced ciliary ache, ciliary spasm, or inducedaccommodation;

all patients achieved 20/30+ visual acuity or better at 14″ and werevery satisfied with their high contrast near vision results and therewas no significant complaint of burning or aching; the duration ofeffect lasted 6-8 hrs in all cases;

binocular vision afforded all patients 1-1.5 additional lines of nearacuity over monocular testing;

the last 10 patients were tested at 20″ (i.e. computer distance, cellphone distance) and all achieved 20/25 or better near visual acuity;

moderately hyperopic (approx. +2.25 sphere) uncorrected presbyopes werevery satisfied with distance visual acuity that improved to a 20/25 orbetter level at distance and near vision in the 20/30 range; and

uncorrected distance acuity was often improved for those patients whochose not to routinely correct a small refractive error.

As seen in Table 5, the use of polyoxyl 40 stearate provides the mostcomfortable aceclidine formulation with the least amount of visual blurand redness. To achieve similar results to that of formula #22, formula#23 requires 10-15% higher concentrations of the non-ionic surfactantand formula #24 requires 15-20% higher concentrations of the non-ionicsurfactant. HPβCD induced a color change over time, possibly indicativeof oxidation. Captisol® (sulfobutylether β-cyclodextrin) was substitutedwith similar findings.

Example 6 Modulation of Aceclidine Concentrations in a PreferredEmbodiment

Preferred embodiment:

Aceclidine 1.35%-1.55% w/v;

Polyoxyl 40 stearate 5.5% w/v;

NaCl 0.037% w/v;

a viscosity enhancer, preferably CMC 0.80% w/v or an amount of Carbopol®934 or 940 sufficient to achieve a viscosity of from about 5 to about 35cps upon topical instillation, such as Carbopol® 940 at a concentrationfrom about 0.09% to about 1.0% w/v;

BAK 0.015% w/v; and

a phosphate, citrate, citrophosphate, or acetate buffer from about 3 toabout 10 mM, wherein the pH is from about 4.75 to about 6.0.

For 1.35% w/v aceclidine—

Stinging on topical instillation 0.25/4.0 (lasting about 2-5 seconds);

Induced redness at 10 minutes: 1.0 to 1.5/4.0;

Induced redness at 30 minutes: 0.0 to 0.25/4.0;

Comfort: very high.

Wetting: very high, the eye maintaining sensation of improved wettingfor most of a 24 hour period after a single topical instillation.

Depth of Focus distance: excellent.

Depth of Focus near: excellent.

In testing the above formulations on several subjects it was discoveredthat there is a slight range in clinical effect depending on theconcentration of aceclidine, where 1.35%-1.55% w/v aceclidine ispreferred, but for which 1.35% w/v and 1.45% w/v confer the desiredbenefits on most subjects.

Further, it is discovered that the clinical effect of 1.35% w/vaceclidine can be improved when instilled as follows:

1) baseline effect: 1 drop to each eye.

2) enhanced effect: 2 drops to each eye.

3) greater effect: after 2) above repeat 1) above.

4) maximum effect: after 2) above repeat 2) above.

Example 7 Use of a Preferred Embodiment to Prolong Contact Lens Wear

Preferred embodiment:

Aceclidine 1.45% w/v;

Polyoxyl 40 stearate 5.5% w/v;

NaCl 0.037% w/v;

a viscosity enhancer, preferably CMC 0.80% w/v or an amount of Carbopol®934 or 940 sufficient to achieve a viscosity of from about 5 to about 35cps upon topical instillation, such as Carbopol® 940 at a concentrationfrom about 0.09% to about 1.0% w/v;

BAK 0.02% w/v; and

a phosphate, citrate, citrophosphate, or acetate buffer from about 3 toabout 10 mM, wherein the pH is from about 4.75 to about 6.0.

As a baseline, the subject, who normally wore extended wear lenses (AirOptix®; Air Optix is a registered trademark of Novartis AG) for dailywear only, slept in these lenses overnight. On arising each morning thesubject's vision was blurred and the contact lenses required removal andcleaning of film and deposits that had formed overnight. Average visionon arising at distance: 20.60; average vision at near on a Michelsoncontrast acuity chart: 20.80.

Then, for seven consecutive days the above formulation was instilledbetween 7 am and 10 am each day as a single dose. Subject wore the AirOptix® lenses throughout each day and slept in the lenses overnight.Upon arising each morning the subject's vision at distance: 20.20+;vision at near 20.40 unaided (consistent with subject's baselinepresbyopia when the subject did not wear the lenses overnight andinstead inserted the lenses upon arising).

Example 8 Comparison of Effects of Polyoxyl 40 Stearate and Captisol®(Sulfobutylether β-Cyclodextrin

TABLE 6 Comparison of Effects of Polyoxyl 40 Stearate and Captisol ®(sulfobutylether β-cyclodextrin). #25 #26 #27 #28 #29 #30 #31 #32 #33Aceclidine  1.35%  1.35%  1.35%  1.35%  1.35%  1.35%  1.35%  1.35% 1.35% Tropicamide 0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044%0.044% 0.044% Polyoxyl 40 stearate  5.5%  5.5%  5.5%  5.5%  5.5%  5.5% 5.5% Captisol ®  5.5%  5.5% Cocamidopropyl betaine  0.10% EDTA 0.015%0.015% 0.005% 0.005% 0.005% 0.005% 0.015% CMC 1% = 2,500 cps  0.80% 0.80%  0.80%  0.80%  0.80%  0.80%  0.80%  0.80%  0.80% NaCl 0.037%0.037% 0.037% 0.037% 0.037% 0.037% 0.037% 0.037% 0.037% Mannitol    4%   4% BAK 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007%Borate buffer (mM) 4 4 4 4 4 4 4 Phosphate buffer (mM) 4 4 pH 7 7 7 7 77 7 7 7 Redness, 10 min 1.25 1.25 2 2 1.75 1.75 0 0 0 Redness, 30 min 00 1.5 1.5 1.25 1.25 0 0 0 Pupil, 30 min (mm) <2 <2 <2 <2 <2 <2 <2 <2 <3Blur on instill (sec) 10 10 10 10 10 10 10 10 10 Ache 0 0 0 0 0 0 1 0 0Rating 4.00 4.00 2.00 2.00 2.50 2.50 1.00 5.00 TBD

As seen in Table 6, when using polyoxyl 40 stearate as the surfactantthe exclusion of EDTA results in reduced redness and best overall ratingamong polyoxyl 40 stearate compositions (Formulas #25 and #26). Theaddition of cocamidopropyl betaine (“CAPB”) further reduces rednesshowever results in significant ache (Formula #31). Replacing polyoxyl 40stearate with Captisol® (sulfobutylether β-cyclodextrin) and addingmannitol achieves similar results in redness reduction as the additionof CAPB to polyoxyl 40 stearate but without the attendant ache resultingin the highest overall rating among aceclidine compositions (Formula#32). After several weeks formulations with Captisol® (sulfobutyletherβ-cyclodextrin) had an orange hue, possibly indicative of oxidation.

Example 9 Preferred Cold Chain Composition

Composition

aceclidine at a concentration of about 1.40%-1.80% w/v; and

tropicamide at about 0.42% w/v;

polyoxyl 40 stearate at about 5.5% w/v;

mannitol at a concentration of about 2.5% to 4.5% w/v;

carbomer 940 at a concentration of about 0.09% to about 2.0% w/v;

optionally, a preservative such as BAK at a concentration of about 0.2%w/v;

optionally citrate at a concentration of about 0.1%;

optionally with acetate or phosphate buffer at 2-100 mM, more preferably3-5 mM

wherein said composition has a pH of about 4.50 to about 5.0; andpreferably, about 4.75 to about 5.0; and

wherein w/v denotes weight by volume

A composition as described above was administered to a 62 year oldsubject. It resulted in pupils of 1.8-1.9 mm ou, 20.20+reading vision,and 20.20+distance vision; whereas without carbomer 940 reducedeffectiveness resulted at 2.5% mannitol, and no near vision effectresulted at 4.0% mannitol. No ciliary spasm or loss of distance visionresulted. Onset was within about 15 minutes. Transient redness of about1+/out of 4 was noted for about 20 minutes without alpha agonistvasoconstrictor. The presence or absence of BAK had no clinical effect,and was used to provide an optional preservative.

Example 10 Stabile Aceclidine Formulations

Composition Tested:

aceclidine at a concentration of about 1.50% w/v;

tropicamide at a concentration of about 0.042% w/v;

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

mannitol at a concentration of about 2.5% w/v;

citrate at a concentration of about 3 mM;

wherein said composition has a pH of about 4.75.

20 samples of the above composition were divided evenly and stored at25° C. and 4° C. Prior to storage, initial concentrations of aceclidinewere measured using high-pass liquid chromatography (“HPLC”). The amountof aceclidine in each solution was calculated by the area under theprincipal peak compared to a reference solution of aceclidine. Sampleswere then subject to storage for 3 months. Aceclidine measurements weretaken at 1, 2 and 3 months. Results of the stability test are shown inTable 7.

TABLE 7 Stability of Aceclidine in Cold Chain Storage 25° C. 4° C.Initial 100% 100% 1 month 92% 93% 2 months 75% 92% 3 months 50% 88%

As seen in Table 7 “cold chain storage” or storage of the aceclidinecomposition at from 2° C. to 8° C. resulted in a significant increase instability of aceclidine at all 3 time points.

Example 11 Use of Compositions Containing Little or No Cycloplegic Agent

Aceclidine alone causes incidence migraine-like severe ciliary spasm(brow ache) and myopic blur. These effects are inversely correlated toage with subjects age 40 reporting the highest incidence and subject age60+ reporting the lowest incidence. The addition of a cycloplegic agentreduces ciliary spasms and attendant brow ache, migranious headache,squeezing pressure around eyes or other symptoms of ciliary spasms. Theaddition of the cycloplegic agent, surprisingly, does not reduce themyopic effect of aceclidine. The addition of 2.5% w/v mannitol howeverdoes reduce the myopic effect of aceclidine. Increasing the aceclidineconcentration overcomes this reduction in myopic effect seen with theaddition of mannitol. Surprisingly, however, the increase in aceclidineis not coincident with an increase in ciliary spasm. Even moresurprising, the concentration of the cycloplegic agent can be reduced oreven eliminated in the presence of mannitol without an increase inciliary spasm. Thus, combining a higher concentration of aceclidine withlittle to no cycloplegic agent in the presence of mannitol results in animprovement of near vision acuity without attendant side effects on parwith lower concentrations of aceclidine and higher concentrations of thecycloplegic agent in the absence of a cycloplegic agent.

Further and unexpectedly, the addition of a nonionic surfactantincreases both the quantitative measure of near vision improvement andthe duration. This effect is concentration sensitive. In a preferredembodiment the non-ionic surfactant is at least 1%, preferably at least2%, more preferably from about 1% to about 5%, and most preferably about5%. For example, polysorbate 80 or polyoxyl 40 stearate at aconcentration from about 1% to about 5% w/v results in about 1.5 toabout 2.0 lines of improvement and a duration from about 4 to about 5hours.

Not to be held to particular theory, the increase in concentration of asurfactant may crowd the surface of the cornea, and at an optimalconcentration this crowding result in small and probably nanometerdiameters, which given the dual polarity of surfactants, where nonionicare most preferred, enhances corneal absorption of the entrapped highlypolar aceclidine molecules.

The further addition of a viscosity enhancer by itself does not enhanceduration. Surprisingly, the addition of a viscosity enhancer in aformulation with optimal ratios of aceclidine, tropicamide and anon-ionic surfactant dramatically improves duration. For example, aformulation of the present invention comprising 1.75% aceclidine, 2.5%mannitol, 0.01% tropicamide, 5% polysorbate 80 improves near vision in apresbyopic patient by up to 3 lines of vision acuity for about 4 toabout 5 hours. The addition of 1.4% CMC further increases the nearvision improvement to from about 7 to about 10 hours. Not to be held toa particular theory, a threshold above the critical micellar thresholdgreatly enhances permeation through the cornea by reducing micelle sizefrom micrometers to nanometers. See FIG. 2.

Examples of compositions containing little or no cycloplegic agent areshown in Table 8 below.

TABLE 8 Compositions containing little or no cycloplegic agent #L1 #L2#L3 #L4 #L5 #L6 #L7 #L8 #L9 #L10 Aceclidine 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75%  1.75%  Tropicamide 0.02% 0.02% 0.02%0.02%  0.02% — — — — — Mannitol  2.5%  2.5%  2.5% 2.5%  2.5%  2.5%  2.5% 2.5% 2.5% 2.5% Polysorbate 80 0.75% 0.25% 0.25% 0.1%  0.1%   0.5%^(#)0.25% 0.25% 0.1% 0.1% Carbopol ® 940 or CMC 0.95% 0.95% 0.95% 0.9% 0.95% 0.95%*  0.95%*  0.95%*  0.9%* 0.95%* Glycerine Phosphate buffer 3 mM —3 mM 3 mM 3 mM 3 mM — 3 mM 3 mM 3 mM NaCl  0.5%  0.1% 0.05% —  0.1%  0.5%^(#)  0.1% 0.05% — 0.1% Boric acid — 0.12%  0.2% 0.2% 0.12% —0.12%  0.2% 0.2% 0.12%  BAK 0.015%  0.01% 0.01% 0.05%  0.01% 0.015% 0.01% 0.01% 0.05%  0.01%  pH 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0#L11 #L12 #L13 #L14 #L15 #L16 #L17 #L18 #L19 #L20 #L21 Aceclidine 1.65%1.65% 1.75% 1.75% 1.65% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide0.01% — — 0.025%  0.025%  0.025%  0.025%  0.025%  0.025%  0.015% 0.015%  Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% 2.5%  2.5% Polysorbate 80   2%   2%   1% 0.10% 2.50% 2.50% 3.00% 2.50%2.50% 2.50% 2.50% Carbopol ® 940 or CMC 0.75% 0.75% 0.75% 0.75% 0.75%0.75% 0.75% 1.50% 0.75% 0.75% 0.75% Glycerine 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.20% 0.20% 0.20% Phosphate buffer 3 mM 3 mM 3mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM NaCl — — — — — — — — — — —Boric acid — — — — — — — — — — — BAK 0.01% 0.01% 0.01% 0.01% 0.015% 0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  pH 5.0 5.0 5.0 5.0 5.255.25 5.25 5.25 5.25 5.25 5.25 #L22 #L23 #L24 #L25 #L26 #L27 #L28 #L29#L30 #L31 #L32 Aceclidine 1.65% 1.75% 1.75% 1.75% 1.75% 1.65% 1.75%1.75% 1.75% 1.75% 1.75% Tropicamide 0.025%  0.275%  0.020%  0.015% 0.027%  0.0275%  0.0275%  0.0275%  0.025%  0.022%  0.0175%  Mannitol 2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%Polysorbate 80   5%   5%   5%   5%   5%   5%   5%   5%   5%   5%   5%Carbopol ® 940 or CMC 1.25% 1.45% 1.45% 1.45% 1.45% 1.25% 1.40% 1.40%1.50% 1.40% 1.50% Glycerine Phosphate buffer 3 mM 3 mM 3 mM 3 mM 3 mM 3mM 3 mM 3 mM 3 mM 3 mM 3 mM NaCl — — — — — — — — — — — Boric acid — — —— — — — — — — — BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% 0.01% 0.01% pH 5.0 5.0 5.0 5.0 6.0 5.0 5.0 5.0 5.0 5.0 6.0 PupilSize (mm) Reading vs. Baseline 40 cm 3+  3+  3+  3+  3+  3+  3+  3+  3+ Duration (hours) 7   10+   10+   10+   10+   7.0 10+   10+   10+  Ciliary Spasms 0.0 tr 0.5 1.0 1.0 0.0 tr 0.5 1.0 1.0 Stinging 0.5 0.50.5 0.5 0.5 0.5 0.5 0.5 0.5 Blur (min) 1   1   1   1   1   1   1   1  1   Distance Blur Onset (min) 20   20   20   20   20   20   20   20  20   Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Redness 4 hr(0-4) Overall Comfort sl sticky sl sticky sl sticky sl sticky sl stickysl sticky sl sticky sl sticky sl sticky Osmolarity Efficacy index read *dur OVERALL (1-5) best best best best best best best best best #L33 #L34#L35 #L36 #L37 #L38 #L47 #L48 #L49 #L50 #L51 Aceclidine 1.75% 1.40%1.40% 1.25% 1.45% 1.45% 1.45% 1.55% 1.65% 1.75% 1.65% Tropicamide — — —— — 0.0200%  — 0.0200%  0.0300%  0.0300%  0.0200%  Brimonidine — — — — —— — — — — — Mannitol — — — — — —  2.5%  4.0%  2.5%  2.5%  2.5%Polysorbate 80 — — — — — — — — — 5.00% — Polyoxyl 40 Stearate — — — — 5.5%  5.5%  5.5%  5.5%  5.5% —  5.5% Citrate 0.10% 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% — 0.10% Glycerine — 0.10% 0.10% 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% CMC — 1.45% 0.75% — 0.85%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% HPMC — — — — — — — — — — —Carbopol ® 940 — — — — — — — — — — — NaCl 0.75% 0.75% 0.50% 0.50% 0.50%0.50% 0.50% 0.50% 0.50% 0.50% 0.00% Boric Acid — — — — — — — — — — —Postassium Borate — — — — — — — — — — — Phosphate buffer 3 3 3 3 3 3 3 33 3 3 Acetate — — — — — — — — — — — pH 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.05.25 5.0 5.0 BAK 0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  0.015% 0.015%  0.015%  0.015%  0.015%  Pupil Size (mm) Reading vs. Baseline 40cm 3 3.25 3 2 3 2.5 1.5 0.5 1.5 1.5 1 Duration (hours) 4 7 4.5 6.5 6 3 24 4 2 Ciliary Spasms 4 4 3 2 3 2 0.5 0.5 0.5 0.5 0.5 Stinging 1.0 1.01.0 1.0 1 1 0.5 1 1 Blur (min) Distance blur none none none none nonenone none none none none none Onset (min) 20-11 20-12 20-13 20-14 20-1520-16 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4) 2.0 1.5 0.5 0.50.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall comfort poor poor poorfair poor poor good good good good good Osmolarity hi hi hi hi hi hi hihi hi hi hi Efficacy index: read * dur 12 23 14 0 20 15 5 1 6 6 2OVERALL (1-5) * **½ * — * ** *** * * * * #L52 #L53 #L54 #L55 #L56 #L57#L58 #L59 #L60 #L61 #L62 Aceclidine 1.65% 1.65% 1.65% 1.75% 1.75% 1.65%1.65% 1.65% 1.65% 1.65% 1.75% Tropicamide 0.0100%  0.0250%  0.0000% 0.0000%  0.0250%  0.0250%  0.0250%  0.0150%  0.0400%  0.0250%  0.0300% Brimonidine — — — — — — — — — — — Mannitol  2.5%  2.5%  2.5%  2.5%  2.5% 2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 80 2.00% 2.50% 2.00%1.00% 0.10% 2.00% 2.50% 2.50% 3.50% 2.50% 3.50% Polyoxyl 40 Stearate — —— — — — — — — — — Citrate — 0.10% — — — — — — — — — Glycerine 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% CMC 0.75%0.85% 0.85% 0.85% 0.85% 0.85% 0.85% 0.75% 0.60% 1.60% 0.60% HPMC — — — —— — — — — — — Carbopol ® 940 — — — — — — — 0.75% 0.60% 0.60% NaCl 0.50%0.50% — — — — — — — — — Boric Acid — — — — — — — — — — — PostassiumBorate — — — — — — — — — — — Phosphate buffer 3 3 3 3 3 3 3 3 3 3 3Acetate — — — — — — — — — — — pH 5.0 5.0 5.0 5.3 5.3 5.3 5.00 5.00 5.005.00 5.00 BAK 0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  0.015% 0.015%  0.015%  0.015%  0.015%  Pupil Size (mm) Reading vs. Baseline 40cm 2.5 3 3 2 1.5 2.5 3 2 1.5 2.5 2.5 Duration (hours) 6 5 6 4 4 6 5.5 73 7 7 Ciliary Spasms 0.5 0.5 2 2 0 0 0 0.5 0 0.5 0.5 Stinging 1 0.5 10.5 0.5 0.5 0.5 0.5 0.25 0.25 0.25 Blur (min) 1.5 1 2 Distance blur nonenone none none none none none none none none none Onset (min) 20-2520-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr(0-4) 0.5 0.5 0.5 0.5 1.0 0.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overallcomfort poor poor poor poor good good good good good good goodOsmolarity hi hi nl nl nl nl nl nl nl nl nl Efficacy index: read * dur15 15 18 8 6 15 17 14 5 18 18 OVERALL (1-5) ** **** **** #L63 #L64 #L65#L66 #L67 #L68 #L69 #L70 #L71 #L72 #L73 Aceclidine 1.65% 1.75% 1.65%1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0250% 0.0250%  0.0250%  0.0275%  0.0275%  0.0275%  0.0250%  0.0180%  0.0160% 0.0160%  0.0150%  Brimonidine — — — — — — — — — — — Mannitol  2.5%  2.5% 2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Polysorbate 802.50% 3.50% 4.00% 5.00% 5.00% 2.00% 2.00% 2.00% 2.25% 4.00% 4.00%Polyoxyl 40 Stearate — — — — — — — — — — — Citrate — — — — — — — — — — —Glycerine 0.10% 0.10% 0.10% — — — — — — — — CMC 0.75% 0.50% 0.75% —1.35% 1.35% 1.45% 1.45% 1.45% 1.45% HPMC — — — — — — — — — — —Carbopol ® 940 0.50% 1.35% — 1.45% — — — — — NaCl — — — — — — — — — — —Boric Acid — — — — — — — — — — — Postassium Borate — — — — — — — — — — —Phosphate buffer 3 3 3 3 3 3 3 3 3 3 3 Acetate — — — — — — — — pH 5.005.00 5.00 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.015%  0.015%  0.015% 0.015%  0.015%  0.015%  0.015%  0.015%  0.01% 0.01% 0.01% Pupil Size(mm) Reading vs. Baseline 40 cm 2 2.5 2 2.75 2.75 2.75 2.75 2.75 2.752.75 3 Duration (hours) 4 5 7 7 5.5 6 7 7 7 7.5 Ciliary Spasms 0.5 0.50.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Stinging 0.5 0.5 0.5 0.5 0.5 0.5Blur (min) 1 Distance blur none none none none none none none none nonenone none Onset (min) 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-2520-25 20-25 20-25 Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 Redness 4hr (0-4) Overall comfort good good good good good good good good goodgood good Osmolarity nl nl nl nl nl nl nl nl nl nl nl Efficacy index:read * dur 8 0 10 19 19 15 17 19 19 19 23 OVERALL (1-5) poor ? **½ ****** ****½ #L74 #L75 #L76 #L77 #L78 #L79 #L80 #L81 #L82 #L83 #L84Aceclidine 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.65%1.40% Tropicamide 0.0150%  0.0150%  0.0120%  0.0110%  0.0100%  0.0000% — 0.0100%  0.0150%  0.0000%  0.0000%  Brimonidine — — — — — 0.015%  — —— — — Mannitol  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% 2.5%  2.5% Polysorbate 80 5.00% 5.00% 5.00% 5.00% 5.00% 5.00% — 6.00%7.00% 0.00% 0.00% Polyoxyl 40 Stearate — — — — — — — — — —  5.5% Citrate— — — — — — — — — — — Glycerine — — — — — — — — — — — CMC 1.45% 1.43%1.43% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40% 0.00% 0.75% HPMC — — — — — — —— — — — Carbopol ® 940 — — — — — — — — — — — NaCl — — — — — — — — 0.50%— — Boric Acid — — — — — — — — — — — Postassium Borate — — — — — — — — —— — Phosphate buffer 3 3 3 3 3 3 3 3 3 3 3 Acetate — — — — — — — — — — —pH 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.01% 0.01% 0.01% 0.01%0.01% 0.01% — 0.01% 0.01% 0.010%  0.010%  Pupil Size (mm) Reading vs.Baseline 40 cm 3.25 3.25 3.5 3.5 3.75 2.5 2.5 2.75 2.5 1 1.5 Duration(hours) 7.5 7.5 7 8 9 8 7 5.5 5 3 3.5 Ciliary Spasms 0.5 0.5 1 1 1 2 20.5 0.5 1 1 Stinging 1.0 Blur (min) 1.5 1.5 1.5 Distance blur none nonenone none none none none none none none none Onset (min) 20-25 20-2520-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4)2.0 Redness 4 hr (0-4) Overall comfort good-exc good-exc good-exc excexc fair fair good good fair Osmolarity nl nl nl nl nl nl nl nl hi nl nlEfficacy index: read * dur 24 24 25 28 34 20 18 15 13 3 5 OVERALL (1-5)***** ***** *****! *****!! *****!! **** **** *** *** * #L85 #L86 #L87#L88 #L89 #L90 #L91 #L92 #L93 #L94 Aceclidine 1.75% 1.75% 1.75% 1.75%1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0000%  0.0100% 0.0900%  0.0060%  0.0060%  0.0100%  0.0060%  0.0060%  0.0060%  0.0060% Brimonidine — — — — — — — — — — Mannitol  2.5%  2.5%  2.5%  2.5%  2.5% 2.5%  2.5%  2.5% —  2.5% Polysorbate 80 5.00%  2.5%  2.5%  2.5%  2.5%2.50% 2.50% 2.75% 2.75% 3.50% Polyoxyl 40 Stearate — — — — — — — — — —Citrate — — — — — — — — — — Glycerine — — — — — — — — — — CMC 1.40% — —— — — — — — — HPMC — 1.75% 1.75% 1.75% 1.75% — — — — — Carbopol ® 940 —— — — — 1.75% 1.75% 1.80% 1.80% 1.80% NaCl 0.00% 0.50% — 0.50% — 0.50%0.50% 0.50% 0.50% 0.50% Boric Acid — — 0.35% — — — — — 0.25% —Postassium Borate — — 0.47% — — — — — 0.37% — Phosphate buffer 3 3 3 3 43 3 3 3 3 Acetate — — — — — — — pH 5.0 5.0 5.0 5.0 6.0 5.0 5.0 5.0 5.05.0 BAK 0.010%  0.020%  0.020%  0.020%  0.020%  0.02% 0.02% 0.02% 0.02%0.02% Pupil Size (mm) Reading vs. Baseline 40 cm 3.5 3.5 3.5 3.75 3.753.5 3.75 3.75 3.75 3.75 Duration (hours) 7 8 7 9 9 7 7 8 8 8.5 CiliarySpasms 2 0.5 0.5 0.5 0.5 0.5 0.5 0 0 0 Stinging 0.5 Blur (min) Distanceblur 2.0 none none none none none none none none none Onset (min) 20-2520-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4)1.0 1.0 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overallcomfort good good good good good Osmolarity nl nl nl nl lo Efficacyindex: read * dur 25 28 25 34 34 25 26 30 30 32 OVERALL (1-5) **** ********** ***** ***** ***** All concentration in weight by volume. mmdenotes millimeters. cm denotes centimeters. min denotes minutes. %*denotes amount can optionally vary from about 0.01% to about 1% w/v. #denotes formulation can include polysorbate 80 or not includepolysorbate 80. Ciliary spasms scores correspond to the following: 0 =no discomfort; 0.5 = slight sting; 1 = noticeable squeeze/discomfort; 2= pain for less than 30 minutes; 3 = pain for 1 hour or more; and 4 =severe to intolerable pain.

The efficacy index is demonstrated in FIG. 3. In brief, the score iscalculated by multiplying the lines of improvement in near visual acuityby the number of hours the improvement lasts. For example a score of: 5is equal to +1 lines of improvement in near visual acuity for 5 hours;10 is equal to +1.5 lines of improvement for 6.7 hours; 15 is equal to 2lines of improvement for 7.5 hours; 20 is equal to 2.5 lines ofimprovement for 8 hours; 25 is equal to 3+ lines of improvement for 8.3hours and 35 is equal to 3.75+ lines of improvement for 9 hours.

As demonstrated by comparing the Reading vs. Baseline at 40 cm andEfficacy Indexes of formulas #L33-#L37, formulas containing 1.40% ormore aceclidine are better at correcting presbyopia than those formulascontaining 1.25% aceclidine. Inversely, the lower concentration ofaceclidine results in better overall comfort to the user. The additionof 2.5% mannitol to formulas with 1.45% aceclidine improves overallcomfort but at the expense of reducing the presbyopic correcting effect(compare #L37 with #L47.) This reduction in near vision improvement isexacerbated with the addition of 4.0% mannitol (compare #L47 with #L48.)Increasing aceclidine concentrations to 1.65% or 1.75% overcome thereduction in near vision improvement seen with the addition of mannitol(compare #L47 with #L49 and #L50.)

Further, formulas containing 1.75% aceclidine and 2.5% mannitol have anincreased efficacy and duration in treating presbyopia that iscorrelated with an increase in polysorbate 80 up to 5.0% and theninversely correlated with a decrease in CMC from 1.45% to 1.40% (compareformulas #L66 to #L78.) Optimal formulations are demonstrated by #L77,#L78 and #L85-#L94, which each have the highest improve reading at 40 cmat between 3.5 and 3.75 visual acuity lines and the highest EfficacyIndex scores of 25 to 34, and the longest duration from 7 to 9 hours.The increase in effectiveness and duration of formulas from #L66 to #L78are also inversely correlated with a decrease in tropicamide from0.0275% to 0.01%. This same trend is demonstrated by the increase ineffectiveness (i.e. Reading vs. Baseline 40 cm) when comparing #L85through #L94.

This data demonstrates that mannitol can effectively reduce ciliaryspasms caused by aceclidine, thus reducing the need for a cycloplegicagent such as tropicamide. Further, this data demonstrates that theaddition of a non-ionic surfactant and viscosity enhancer can furtherenhance the efficacy and duration of compositions containing aceclidine,mannitol and low tropicamide. This data also demonstrates that the useof a cycloplegic agent in aceclidine compositions containing polysorbate80 and CMC is most beneficial to presbyopic correction when thecycloplegic agent is closer to 0.006% than 0.025%. Finally, this datademonstrates that compositions comprising aceclidine and mannitol aresufficient to correct presbyopia with tolerable pain.

Example 12 Use of Further High Tropicamide Formulations

The following examples are of aceclidine formulations containing morethan 0.03% tropicamide.

TABLE 9 High tropicamide formulations #L39 #L40 #L41 #L42 #L43 #L44 #L45#L46 Aceclidine 1.45% 1.45% 1.40% 1.40% 1.40% 1.40% 1.40% 1.40%Tropicamide 0.035%  0.037%  0.040%  0.050%  0.055%  0.06% 0.08% 0.04%Polyoxyl 40  5.5%  5.5%  5.5%  5.5%  5.5%  5.5%  5.5%  5.5% StearateCitrate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Glycerine 0.10%0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% CMC 0.75% 0.75% 0.75% 0.75%0.75% 0.75% 0.75% 0.75% NaCl 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50%0.50% Phosphate buffer 3 3 3 3 3 3 3 3 pH 5.0 5.0 5.0 5.25 5.5 5.25 5.05.0 BAK 0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  0.015%  0.015% Reading vs. 3.5 3.5 3.5 2 1 1 1 3 Baseline 40 cm Duration (hours) 6 6 62 2 1 1 6 Ciliary Spasm 1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Stinging 1.0 1.01.0 0.5 0.25 0.5 1 1 Distance blur none none none none none none nonenone Onset (min) 20-17 20-18 20-19 20-20 20-21 20-22 20-23 20-24 Redness1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Overall comfort fair goodgood good good good good good Osmolarity hi hi hi hi hi hi hi hiEfficacy index: 21 21 21 4 2 1 1 18 read * dur OVERALL (1-5) ** ****** * ½* ¼* ¼* *** Ciliary spasms scores correspond to the following: 0= no discomfort; 0.5 = slight sting; 1 = noticeable squeeze/discomfort;2 = pain for less than 30 minutes; 3 = pain for 1 hour or more; and 4 =severe to intolerable pain.

As demonstrated by formulas #L39-#L41 and compared to formulas #L74-#L78in Table 8, formulas containing about 1.40% to about 1.45% aceclidine,about 0.035% to about 0.04% tropicamide, about 5.5% polyoxyl 40 stearateand about 0.75% CMC are almost, but not quite as effective at treatingpresbyopia as formulas containing about 1.65% to about 1.75% aceclidine,about 2.5% mannitol, about 5% polysorbate 80, about 1.40% CMC formulas.This effectiveness decreases dramatically when tropicamide is increasedto about 0.05% to about 0.08% tropicamide.

Example 13 Use of a Compound Containing Mannitol

Formulation:

aceclidine 1.75% w/v

tropicamide 0.006% w/v

mannitol 2.5% w/v

polysorbate 80 2.75% w/v

NaCl 0.5% w/v

hydroxypropylmethyl cellulose 1.80% w/v

phosphate buffer 3 mM

pH 5.0, and

BAK 0.020% as preservative.

Method:

The subject instilled 2 drops of the above formulation in each eye andthe excess wiped from lids and lashes.

Results:

Within 20 minutes, near vision improvement of about 3 lines of visualacuity was noted with very slight dimming. Throughout the day nearvision remained enhanced with no loss of distance vision. Further, ifthe subject previously suffered from any mild refractive errors distancevision was improved. Over a 5-8 hour period the pupil begins to slightlyrecover, and after a few hours the minimal dimming was no longer noted.Both excellent near vision near onset, and possibly still slightlyimproved near vision continued as the pupil slightly begins to increasefrom its minimal size earlier in the day.

Example 14 Use of a Preferred Embodiment Optimizing Tropicamide andHydroxypropyl Methyl Cellulose

Composition

Aceclidine 1.75% w/v Tropicamide 0.010% w/v Mannitol 2.50% w/vPolysorbate 80 3.50% w/v NaCl 0.50% w/v HPMC 1.80% w/v BAK 0.02% w/vPhosphate buffer 3 mM pH 5.00Method

The subject instilled 2 drops of the above formulation in each eye andthe excess wiped from lids and lashes.

Results:

Comfort, duration and efficacy were assessed. Stinging upon instillationand over the first hour was minimal with a score of 0.25 out of 4.Redness over the first hour was also minimal with a score of 0.5 out of4. Onset of vision improvement occurred with the first 20 to 25 minutesafter instillation. Baseline near vision (i.e. 40 centimeters) wasimproved by 3.5 lines of visual acuity. Improvement in near visionlasted for 8.5 hours. Comparing this formula to those in Table 8, theEfficacy Index score was 29.75. Substituting HPMC 1.80% w/v with HPMC1.65% w/v resulted in a slight reduction in near vision improvement to3.25 lines of visual acuity and a slight reduction in duration to justover about 6 hour. Comparing this formula to those in Table 8, theEfficacy Index score was 19.5.

Example 15 Use of a Compound Containing Mannitol with Various NonionicSurfactants Compositions

Table 10 lists the active ingredients, excipients and theirconcentrations for compositions with both tested and prophetic examplesof nonionic surfactants.

Methods

The subject independently instilled 2 drops of the above compositions ineach eye and the excess wiped from lids and lashes.

Results

All nonionic surfactants tested demonstrate substantial near visionimprovement. Of those tested only Brij® 35 was marginal due to thesignificant corneal irritation, hyperemia and reduced duration thatresulted. Polysorbate 80 and poly 35 castor oil were most preferred,polyoxyl 40 stearate and poloxamer 407 excellent as well. However,polyoxyl 40 stearate caused a precipitate reaction with celluloseviscosity agents and added other stability issues.

Comfort and duration for each non-ionic surfactant were also tested andare noted in Table 10. Stinging and Redness are based on a scale of 0 to4 with 0 being none and 4 being the most severe. Other than Brij® 35stinging and redness were mild to nearly absent. Duration was excellentfor each nonionic surfactant tested.

TABLE 10 Comparing efficacy and comfort of various nonionic surfactantsPolysorbate Polyoxyl 35 Polyoxyl 40 Poloxamer Tyloxapol Polysorbate 20Poloxamer 188 Solulan C-24 % w/v 80 castor oil stearate 407 Brij ® 35(prophetic) (prophetic) (prophetic) (prophetic) Aceclidine 1.75% 1.75%1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.006%  0.006% 0.005%  0.005%  0.005%  0.006%  0.006%  0.006%  0.006%  Mannitol  2.5% 2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5%  2.5% Nonionic  3.5%  3.5% 3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5% surfactant NaCl 0.50% 0.50%0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% HPMC 1.80% 1.80% 1.80% 1.80%1.80% 1.80% 1.80% 1.80% 1.80% BAK 0.02% 0.02% 0.02% 0.02% 0.02% 0.02%0.02% 0.02% 0.02% Phosphate buffer 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3mM 3 mM pH 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Stinging 0.25 00.5 0.5 2 0-2 0-2 0-2 0-2 Redness 1 hr 0.5 0.25 0.75 1 2.5 0.25-2.5 0.25-2.5  0.25-2.5  0.25-2.5  Reading vs. 3.75 3.5 3 3 2   2-3.5   2-3.5  2-3.5   2-3.5 Baseline (40 cm) Duration (hours) 10 9 7 7 4 4-8 4-8 4-84-8 Efficacy Index 37.5 31.5 21 21 8   8-37.5   8-37.5   8-37.5   8-37.5read * dur Onset (min) 20-25 20-25 20-25 20-25 30-40 20-40 20-40 20-4020-40

What is claimed is:
 1. An ophthalmological composition for the treatmentof presbyopia comprising: an active agent consisting of from about 0.25%to about 2.0% w/v aceclidine; and a polyol, wherein w/v denotes weightby volume.
 2. The ophthalmological composition according to claim 1,wherein the polyol is mannitol at a concentration from about 1.0% toabout 10.0% w/v.
 3. The ophthalmological composition according to claim2, further comprising a nonionic surfactant.
 4. The ophthalmologicalcomposition according to claim 3, wherein the nonionic surfactant isselected from the group consisting of a polysorbate, a polyoxyl castoroil, a polyoxyl stearate, a poloxamer, a polyethylene glycol, apolyoxyethylene glycol alkyl ether, tyloxapol and2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol.5. The ophthalmological composition according to claim 4, wherein thenonionic surfactant is polysorbate 80 or polyoxyl 35 castor oil.
 6. Theophthalmological composition according to claim 5, wherein the nonionicsurfactant is polysorbate 80 at a concentration from about 0.5% to about10.0% w/v.
 7. The ophthalmological composition according to claim 3,further comprising a viscosity enhancer.
 8. The ophthalmologicalcomposition according to claim 7, wherein the viscosity enhancer isselected from the group consisting of a cellulose derivative,hyaluronate, a carbomer and a gum.
 9. The ophthalmological compositionaccording to claim 8, wherein the viscosity enhancer is at aconcentration from about 1.0% to about 2.0% w/v and wherein w/v denotesweight by volume and wherein initial viscosity of the composition isfrom about 25 to about 10,000 centipoise.
 10. The ophthalmologicalcomposition according to claim 7, further comprising a preservativeselected from the group consisting of benzalkonium chloride, sorbicacid, oxychloro complex and a combination thereof.
 11. Anophthalmological composition for the treatment of presbyopia comprising:about 1.65% to about 1.80% w/v aceclidine; and about 2.0% to about 3.0%w/v polyol, wherein w/v denotes weight by volume.
 12. Theophthalmological composition of claim 11 further comprising about 2.0%to about 6.0% w/v nonionic surfactant.
 13. The ophthalmologicalcomposition of claim 12 further comprising about 0.5% to about 2.0% w/vviscosity enhancer.
 14. The ophthalmological composition of claim 13further comprising about 0.004% to about 0.007% w/v cycloplegic agent.15. An ophthalmological composition for the treatment of presbyopiacomprising: about 1.75% w/v aceclidine as the sole active agent; andabout 2.5% w/v mannitol, wherein w/v denotes weight by volume.
 16. Theophthalmological composition of claim 15 further comprising one or moreexcipients selected from the group consisting of about 0.50% w/v sodiumchloride, about 0.02% w/v benzalkonium chloride, about 0.10% w/vsorbate, about 0.01% w/v ethylenediaminetetraacetic acid (EDTA) and0.10% w/v citric acid.
 17. A method of treating presbyopia comprisingadministering to a subject in need thereof the ophthalmologicalcomposition of claim
 1. 18. A method of treating presbyopia comprisingadministering to a subject in need thereof the ophthalmologicalcomposition of claim 15, wherein near vision acuity of the subject isimproved by at least 3 lines of resolution for at least 6 hours.
 19. Amethod of treating irregular astigmatism, keratoconic ectasia, and lowmyopia, or hyperopia, with or without astigmatism, comprisingadministering to a subject in need thereof the ophthalmologicalcomposition of claim 1.